Modified Oligonucleotide and Its Preparation and Application

ABSTRACT

The present invention relates to a modified oligonucleotide, its preparation and application. The invention enables stabilizing the oligonucleotide by introducing a relatively small amount of modified nucleotide at specific UA/UA and/or CA/UG and/or UG/CA site of the oligonucleotide, therefore to decrease the modification-related cytotoxicity and compromising effects on the biological activity.

FIELD OF THE INVENTION

This invention relates to nucleic acid technology, specifically to modified oligonucleotide and its preparation, its application in RNA interference, pharmaceutical compositions, and disease treatment.

BACKGROUND OF THE INVENTION

RNA interference (RNAi) is a gene silencing phenomenon mediated by double-stranded RNA (dsRNA) molecules, shutting down homologous gene expression at mRNA level. RNAi is a post-transcriptional gene regulation mechanism, also named post-transcriptional gene silencing (PTGS), target gene knockdown, or gene silencing.

RNAi phenomenon was first reported in plants by two different research groups in 1990. Later on, this phenomenon was further observed in almost all eukaryotes, including C. elegans, Drosophila, zebrafish and mice.

In 1999, RNA fragments of 21 to 25 nucleotides in length were identified in plant RNAi by Hamilton and Baulcombe. These small RNA fragments were demonstrated to be the mediator necessary for RNAi, and thus named as small interfering RNA (siRNA).

Double-stranded siRNA conjugates with endogenous enzymes and proteins, and then forms RNA-induced silencing complex (RISC). In the process of RNAi, while the sense RNA strand of double-stranded siRNA is excluded from the complex, the antisense RNA strand functions to guide RISC to target mRNA at homologous locus, resulting in the degradation of target mRNA and gene silencing mediated by RNase III component within RISC complex.

However, due to the vulnerability of siRNA to serum ribonuclease that resulting in serum instability, synthetic siRNAs are often chemically modified so as to increse their serum stability and gene silencing activity.

Even though, in consideration of the poor understanding of the degradation process and mechanism of RNAi, random modification strategy is performed to stabilize siRNA in body fluids. Although this strategy can improve serum stability of the modified siRNAs to some extent, it usually ends up with excessive chemical modifications and results in increased cytotoxicity and compromised biological activity in many cases, due to the lack of theoretical guidance. This therefore restricts the in vivo applications of the modified siRNAs. In addition, the extensive siRNA modification strategy also limits the use of many chemical modifications that have great stabilizing effect, however with relatively high cytotoxicity.

Therefore, there is an urgent need to develop a specific modification strategy for synthetic siRNAs, to achieve optimum serum stability with minimal chemical modifications.

SUMMARY OF THE INVENTION

The present invention is to overcome technical problem caused by the extensive siRNA modification commonly performed in the art, by providing a kind of modified oligonucleotide. The oligonucleotides provided in the present invention include, without limitation, RNA and DNA oligonucleotides, also include a variety of chemically modified nucleic acid derivatives including single-stranded and double-stranded nucleic acid molecules. That is, the modified oligonucleotides disclosed in the invention include but do not limit to single-stranded RNA molecules (ssRNA), single-stranded DNA molecule (ssDNA), double-stranded RNA molecules (dsRNA), double-stranded DNA molecule (dsDNA), as well as a variety of nucleic acid derivatives modified from the above molecules. Preferably, the oligonucleotides are double-stranded RNA molecules (dsRNA); more preferably, the oligonucleotides are small interfering nucleic acids (siRNA).

To address these problems, the present invention discloses a modified oligonucleotide comprising a first nucleic acid fragment and a second nucleic acid fragment. Said first nucleic acid fragment and second nucleic acid fragment can form double-stranded region, wherein the modified oligonucleotide has at least one of the following modifications, the modification(s) improve the stability of the modified oligonucleotide in mammalian body fluids:

(a) The first nucleic acid fragment contains at least one contiguous UA sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence in the first nucleic acid fragment. The UA sequence(s) of the first nucleic acid fragment and the complementary UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s); wherein at least one of the nucleotides in at least one of the UA/UA site(s) is a modified nucleotide;

(b) The first nucleic acid fragment contains at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous CA or UG sequence complementary to the CA or UG sequence in the first nucleic acid fragment, the CA or UG sequence(s) of the first nucleic acid fragment and the CA or UG sequence(s) of the second nucleic acid fragment pair to form CA/UG and/or UG/CA site(s); wherein at least one of the nucleotides in at least one of the CA/UG and/or UG/CA site(s) is a modified nucleotide;

(c) The first nucleic acid fragment contains at least one contiguous UA sequence and at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence of the first nucleic acid fragment and one contiguous CA or UG sequence complementary to the CA or UG sequence of the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s), the CA or UG sequence(s) of the first nucleic acid fragment and the UG or CA sequence(s) of the second nucleic acid fragment pair to form CA/UG or UG/CA site(s); wherein at least one of the nucleotides in at least one of the UA/UA site(s) is a modified nucleotide, and at least one of the nucleotides in at least one of the CA/UG or UG/CA site(s) is a modified nucleotide.

According to the present invention, in the cases that the first nucleic acid fragment contains at least one contiguous UA sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence in the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the complementary UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s), modification can be made for at least one of the nucleotides in one UA/UA site, modification can also be made for at least one of the nucleotides in multiple UA/UA sites, modifications can also be made for multiple nucleotides in multiple UA/US sites. Preferably, only one uracil nucleotide is modified in each UA/UA site.

In the cases that first nucleic acid fragment contains at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous CA or UG sequence complementary to the CA or UG sequence in the first nucleic acid fragment, the CA or UG sequence(s) of the first nucleic acid fragment and the CA or UG sequence(s) of the second nucleic acid fragment pair to form CA/UG and/or UG/CA site(s), modification can be made for at least one of the nucleotides in one CA/UG or UG/CA site, modification can also be made for at least one of the nucleotides in multiple CA/UG or UG/CA site(s), furthermore, modifications can also be made for multiple nucleotides in multiple CA/UG or UG/CA sites. Preferably, only one cytosine nucleotide is modified in each CA/UG or UG/CA site.

In the cases that the first nucleic acid fragment contains at least one contiguous UA sequence and at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence of the first nucleic acid fragment and one contiguous CA or UG sequence complementary to the CA or UG sequence of the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s), the CA or UG sequence(s) of the first nucleic acid fragment and the UG or CA sequence(s) of the second nucleic acid fragment pair to form CA/UG or UG/CA site(s), modification can be made for at least one of the nucleotides in UA/UA and CA/UG or UG/CA site; modification can also be made for at least one of the nucleotides in at least one of the UA/UA sites, at the same time, modification is also made for at least one of the nucleotides in at least one of the CA/UG or UG/CA sites.

In the present invention, the term “first nucleic acid fragment” refers to a nucleic acid fragment partly or completely homologous to the coding region of a target gene, the term “second nucleic acid fragment” refers to a nucleic acid fragment complementary to the coding region of a target gene. The term “complementary” refers to that two nucleotides can pair with each other in hybridization condition. For example, adenine (A) can pair with thymine (T) or uracil (U), cytosine (C) can pair with guanine (G).

In the present invention, said oligonucleotides can be small interfering RNA (siRNA) against a variety of target genes. For example, target genes can be an endogenous gene to be studied, a gene whose expression to be inhibited; for example, a gene associated with a disease or a disorder, such as oncogenes, viral genes, cell surface receptors, nuclear receptors, or genes implicated in cellular signaling pathway.

Based on the sequence of a target gene, specific siRNAs can be designed by person having ordinary skill in the art to which this invention belongs. For example, input target gene sequences or their NCBI Genbank sequence number into various siRNA design softwares, such as Insert Design Tool for the shRNA Vectors (Ambion), shRNA Explorer (Gene Link), siDirect (Yuki Naito et al. University of Tokyo), SiRNA at Whitehead (Whitehead Institute for Biomedical Research), BLOCK-iT RNAi Designer (invitrogen), RNAi Design (IDT), RNAi Explorer (Gene Link), siRNA Target Finder (Ambion), or siSearch (Stockholm Bioinformatics Center) etc., the software can design gene-specific siRNAs according to the requirements and siRNA design principles.

In addition, several siRNA design software can also perform genome-wide or transcriptome-wide homology search, so as to obtain target gene-specific or sequence-specific siRNAs. Said siRNA design software and principles are commonly understood by person having ordinary skill in the art to which this invention belongs. All these information are therefore included in the present invention as references.

In a preferred embodiment, the invention relates to a modified oligonucleotide, wherein all the nucleotides are unmodified nucleotides except the nucleotides in said CA/UG and/or UA/UA and/or UG/CA site(s). In these cases, incorporation of minimal chemical modifications into the modified oligonucleotide not only increase its stability, maintain its biological activity, further reduces potential cytocoxicity caused by extensive chemical modifications.

In the present invention, the modified oligonucleotide can be single-stranded or double-stranded oligonucleotide. In the cases of single-stranded oligonucleotide, said first nucleic acid fragment and second nucleic acid fragment can form double-stranded region by base-pairing of their complementary sequences. In the cases of double-stranded oligonucleotide, said modified oligonucleotide can contain a sense strand and antisense strand. The sense strand can be a contiguous fragment, or several discontiguous fragments; the antisense strand is a contiguous fragment.

In one aspect of the present invention, the invention relates to a modified oligonucleotide comprising a sense strand and an antisense chain. Said sense strand and antisense strand are contiguous nucleic acid fragments, said first nucleic acid fragment is in the sense strand, and said second nucleic acid fragment is in the antisense strand.

In another aspect of the present invention, the invention relates to a modified oligonucleotide comprising a sense strand and an antisense strand. Said sense strand comprises two or more discontiguous sense-strand fragments, said antisense strand is a contiguous nucleic acid fragment. Said first nucleic acid fragment is in the one or more sense-strand fragments, and the second nucleic acid fragment is in the antisense strand.

In the present invention, the term “sense strand” refers to a nucleic acid fragment partly or completely homologous to the coding region of a target gene, in the cases that the modified oligonucleotide is a double-stranded molecule. The term “second nucleic acid fragment” refers to a nucleic acid fragment complementary to the coding region of a target gene, in the cases that the modified oligonucleotide is a double-stranded molecule. In addition, in the cases that said modified oligonucleotide is a double-stranded molecule, said sense strand and antisense strand are contiguous nucleic acid fragments, the term “sense strand” and the term “first nucleic acid fragment” are used interchangeably, the term “antisense strand” and the “second nucleic acid fragment” are used interchangeably.

In the present invention, the term “sense-strand fragment” refers to the component fragments of the sense strand, in the cases that said sense strand comprises discontiguous fragments; the total length of all sense-strand fragments is equal to length of the sense strand.

In addition, in the cases that said sense strand contains UA/UA site(s), the term “sense-strand fragment” and “first nucleic acid fragment” are used interchangeably.

In the present invention, said modified oligonucleotide can comprise only ribonucleotides, can also be a hybrid molecule comprising ribonucleotides and at least one deoxyribonucleotide.

In present invention, the term “potential toxicity” refers to the cellular toxicity effects caused by involved chemical modification(s) made on the modified nucleotide(s). In another word, it refers to the inhibition effects on cell growth, and thus named as “growth inhibition ratio” throughout this invention. The higher the growth inhibition ratio is, the greater the potential cytotoxicity is.

In the invention, said modifications are commonly understood by person having ordinary skill in the art to which this invention belongs. For example, the modification(s) are one or a combination of the following modifications:

(a) modifying the phosphodiester bond(s) connecting nucleotides in the oligonucleotide;

(b) modifying the sugar(s) of the nucleotide in the oligonucleotide;

(c) modifying the base(s) of the nucleotide in the oligonucleotide.

Said modification of phosphodiester bond is made by modifying the oxygen of the phosphodiester bond, including phosphorothioate modification and boranophosphate modification. As shown in the figures, these modifications replace the oxygen of the phosphodiester bond by sulfur or boron, respectively. Both modifications can stabilize the structure of siRNA, maintain high specificity and affinity of base pairing. However, boranophosphate siRNAs have stronger hydrophobicity and readily to form protein conjugate in the plasma, and less toxic to human body than phosphorothioate siRNAs.

Said modification of ribose refers to modifications of hydroxyl at 2′-position of the pentose sugars in siRNAs. Replacing the 2′-OH by methoxy or fluorine interfers with the interaction between the modified siRNA and serum ribonuclease, render the siRNA more stable in serum, and increase its resistance to nuclease degradation. Modifications of the 2′-hydroxyl of the pentose sugars comprises 2′-deoxy-2′-fluoro modification (2′-F), 2′-O-methyl modification (2′-OME), 2′-methoxyethyl-modification (2′-MOE), 2,4′-dinitrophenol-modification (2′-DNP), locked nucleic acid (LNA), 2′-amino modification (Amina modification), 2′-deoxy modification, etc.

Said base modification refers to modifications of the base of the nucleotide, including commonly used modifications such as 5′-bromo-uracil and 5′-iodo-uracil, and other modifications such as N3-methyl-uracil and 2,6-diaminopurine, and so on.

Preferably, modified oligonucleotide provided in the present invention is a 2′-modified nucleotide. More preferably, the modified nucleotide is a 2′-OMe-modified or 2′-Fluoro-modified nucleotide. These modifications are made to increase the stability of the modified oligonucleotides in mammalian body fluids and enhance their resistance to nuclease degradation.

The present invention also relates to a method for preparing said modified oligonucleotide, comprising the steps of: selecting UA/UA and/or CA/UG site(s) from the oligonucleotide sequence to be prepared, synthesizing the oligonucleotide, wherein repalcing nucleotide(s) in the selected site(s) by corresponding modified nucleotide(s). The resulting oligonucleotide comprises a first nucleic acid fragment and a second nucleic acid fragment, the first nucleic acid fragment and the second nucleic acid fragment form double-stranded region. (a) said first nucleic acid fragment contains at least one contiguous UA sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence in the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the complementary UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s), wherein at least one of the nucleotides in said UA/UA site(s) is a modified nucleotide; more preferably, only one uracil nucleotide in each UA/UA site is a modified nucleotide.

(b) The first nucleic acid fragment contains at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous CA or UG sequence complementary to the CA or UG sequence in the first nucleic acid fragment, the CA or UG sequence(s) of the first nucleic acid fragment and the CA or UG sequence(s) of the second nucleic acid fragment pair to form CA/UG and/or UG/CA site(s), wherein at least one of the nucleotides in said CA/UG and/or UG/CA site(s) is a modified nucleotide; more preferably, only cytosine nucleotide(s) in CA/UG or UG/CA site(s) is/are modified nucleotide(s).

(c) The first nucleic acid fragment contains at least one contiguous UA sequence and at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence of the first nucleic acid fragment and at least one contiguous CA or UG sequence complementary to the CA or UG sequence of the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s), the CA or UG sequence(s) of the first nucleic acid fragment and the UG or CA sequence(s) of the second nucleic acid fragment pair to form CA/UG or UG/CA site(s); wherein at least one of the nucleotides in said UA/UA and CA/UG and/or UG/CA site(s) is a modified nucleotide; or, at least one of the nucleotides in said UA/UA site is a modified nucleotide, and at the same time, at least one of the nucleotides in said CA/UG and/or UG/CA site(s) is a modified nucleotide.

In a preferred embodiment, the present invention relates to a modified oligonucleotide prepared by the claimed method in the invention, wherein all the nucleotides are unmodified nucleotides except the nucleotides in said UA/UA and/or CA/UG and/or UG/CA site(s).

In the invention, the structures of said oligonucleotides prepared by the provided method are commonly understood by person having ordinary skill in the art to which this invention belongs. Said structures can be any structure of existing nucleotide or oligonucleotide.

For example, the invention relates to a modified oligonucleotide that is prepared by the claimed method in the present invention can be a hairpin-structured and single-stranded nucleic acid molecule, the complementary nucleic acid sequences of the first nucleic acid fragment and the second nucleic acid fragment pair to form double-stranded region. In another aspect, the invention relates to a modified oligonucleotide that is prepared by the claimed method in the invention can contain a sense strand and an antisense strand, the sense strand and the antisense strand are contiguous nucleic acid fragments. Said first nucleic acid fragment is in the sense strand, said second nucleic acid fragment is in the antisense strand.

In yet another aspect, the invention relates to a modified oligonucleotide that is prepared by the claimed method in the present invention can contain a sense strand and an antisense strand. The sense strand contains two or more discontiguous sense-strand component fragments, the antisense strand is a contiguous nucleic acid fragment. Said first nucleic acid fragment is in one or more sense-strand component fragments, the second nucleic acid fragment is in the antisense strand.

In yet another aspect, the invention relates to a modified oligonucleotide that is prepared by the claimed method in the present invention can be a hybrid nucleic acid molecule comprising ribonucleotides and at least one deoxyribonucleotide.

In general, the oligonucleotides of the present invention can be synthesized using conventional protocols known in the art. Alternatively, synthesis can be performed by specialized biotechnology companies providing oligonucleotide synthesis service, such as Shanghai GenePharma Ltd, Guangzhou Ribo Biotechnology Ltd, or Invitrogen Ltd.

In general, the procedure of oligonucleotide synthesis comprises the steps of: (a) Synthesis of oligonucleotide; (b) Deprotection; (c) Purification; and (d) Desalination.

For example, detailed procedure of synthesizing a siRNA comprises the steps of:

(a) Synthesis of oligonucleotide. Single-stranded RNA oligonucleotide is produced by solid phase synthesis on a scale of 1 mmol, using an automatic DNA/RNA synthesizer (for example, Applied Biosystems EXPEDITE8909). Coupling time is set to 10-15 minutes for each synthesis cycle. From the starting material of 5′-O-dimethoxy-thymidine solid support, the first nucleotide is connected to the support in the first synthesis cycle; and for each following synthesis cycle, a new nucleotide is connected to the product of cyclte n-1. Repeat the synthesis cycle until the completion of the synthesis of the oligonucleotide.

(b) Deprotection. Move siRNA-conjugated solid support into a test tube, and add 1 ml of ethanol/triethylamine (volume ratio of 1:3) in the test tube; seal the tube and place it in an incubator at 55 to 70° C., incubate for 2 to 30 hours; take out the siRNA-conjugated solid support and wash twice with double-distilled water (1 ml for each wash); collect the eluate and dry at room temperature for 30 minutes. Then, add 1 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran solution, react at room temperature for 4 to 12 hours; add 2 ml ethanol and collect the sediment for obtaining the crude product of synthesized oligonucleotide.

(c) Purification. Dissolve the obtained crude oligonucleotide in 2 ml ammonium acetate solution (1 mole/ml), separate the oligonucleotide using C18 high pressure liquid chromatography for purified product oligonucleotide.

(d) Desalination. To further remove salt from the oligonucleotide, wash the purified oligonucleotide product 2 to 4 times by ethanol solution (2 ml per wash, 75% in weight ratio), and dry the oligonucleotide product at room temperature. Then, dissolve the sense strand and the antisense strand in 1 to 2 ml annealing buffer (10 mM Tris, pH 7.5-8.0, 50 mM NaCl), heat the solution to 95° C. and let it cool down slowly to room temperature, and keep the solution at room temperature for 16 to 22 hours for obtaining desalted siRNA solution.

The present invention also relates to a pharmaceutical composition for inhibiting the expression of a target gene in a mammal. Said pharmaceutical composition comprises at least one of the modified oligonucleotides disclosed in the invention, and at least one of pharmaceutically acceptable carriers. As used herein, “pharmaceutically acceptable carrier” should be compatible with the oligonucleotide(s) included in said pharmaceutical composition. In general, the “pharmaceutically acceptable carrier” can blend with the oligonucleotide(s) and do not significantly compromise the inhibition activity of the pharmaceutical composition on gene expression, under normal circumstances.

Examples of the substance of “pharmaceutically acceptable carrier” or components of the “pharmaceutically acceptable carrier” are sugars, such as lactose, glucose and sucrose; starch such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl fiber sodium, ethyl cellulose and methyl cellulose; West tragacanth powder; malt; gelatin; talc; solid lubricant such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols such as propylene glycol, glycerol, sorbitol, mannose alcohol and polyethylene glycol; alginate; emulsifiers such as Tween; wetting agents, such as lauryl sulfate sodium; colorants; flavoring agent; pressure tablets, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic salt solution; and phosphate buffer, etc. Preferably, the carriers are selected from saline, glycerol and phosphate phosphate buffer saline.

The pharmaceutical composition provided by the invention can be made in a variety of medically acceptable formulations, and administrated by physicians in an optimal dosage according to patient's type, age, weight, disease condition, delivery approach and other factors. The formulations provided by the present invention includes a variety of liquid formulations such as oral, injection, sublingual agent, tablet formulations prepared by adding suitable excipient, capsule formulation, or a variety of other formulations, etc. Preferred formulations of said pharmaceutical composition comprise injection, capsules, sublingual, oral liquid, aerosol, or patch.

In another aspect, the invention also provides a method for preparing the pharmaceutical composition, said method comprises formulating the modified oligonucleotides and pharmaceutically acceptable carriers to obtain the said pharmaceutical compositions. No particular order or rules need to be applied to the mixing of the modified oligonucleotides and the pharmaceutically acceptable carriers.

In another aspect, the invention also relates to a method for inhibiting the expression of a target gene in a cell, compreseing:

(a) introducing the modified oligonucleotide(s) into at least one of the cells; and

(b) incubating the cells for a time sufficient to obtain inhibition of the expression of the target gene in the cell.

Preferably, the cells are mammalian cells.

The present invention also relates to a method for preparing an oligonucleotide that is highly stable in a biological sample and can inhibite the expression of a target gene, comprising the steps of:

(a) selecting one or more nucleic acid sequences of 18 to 30 nucleotides in length from the nucleotide sequence of the mRNA resulting from the transcription of the target gene; and

(b) synthesizing the selected sequences, wherein one strand comprises a sequence complementary to selected sequence in (a); and

(c) testing one or more oligonucleotides of (b) for their activity to inhibit the expression of the target gene in a biological sample; and

(d) selecting one or more oligonucleotides of (c) possessing the activity to inhibit the expression of the target gene in a biological sample; and

(e) in the oligonucleotides selected in (d), identifying in the nucleotide sequences of all occurrences of the UA/UA, CA/UG and UG/CA site(s); and

(f) synthesizing one or more oligonucleotides selected in (d), wherein at least one nucleotide in the UA/UA, CA/UG and UG/CA site(s) identified in (e) is replaced by its corresponding modified nucleotide.

Preferably, only cytidine nucleotide(s) in all occurrences of the CA/UG or UG/CA site is/are modified, only one uracil nucleotide in each UA/UA site is modified; more preferably, all the nucleotides are unmodified nucleotides except the nucleotides in said CA/UG and/or UA/UA and/or UG/CA site(s).

A method of treating a disease caused by expression of a target gene in a subject is provided in the present invention. Said method comprises administering to said subject a pharmaceutical composition comprising at least one of said oligonucleotides and a pharmaceutically acceptable carrier. Preferably, the subject is mammalian; more preferably, the subject is human being.

The present invention also relates to a method for preparing an oligonucleotide with nuclease resistance, said method comprises the steps of:

(a) identifying in the nucleotide sequence of the oligonucleotide all occurrences of UA/UA, CA/UG and UG/CA site(s); and

(b) synthesizing the oligonucleotide, wherein replaces nucleotide(s) in the UA/UA, CA/UG and UG/CA site(s) identified in (a) by corresponding modified nucleotide(s). Preferably, only cytidine nucleotide(s) in all occurrences of the CA/UG or UG/CA site(s) identified in (a) is/are modified, only one uracil nucleotide in each UA/UA site identified in (a) is modified. More preferably, all the nucleotides are unmodified nucleotides except the nucleotides in said CA/UG and/or UA/UA and/or UG/CA site(s).

The invention also relates to a method to identify an oligonucleotide with stability in biological samples, comprising the steps of:

(a) providing a first modified oligonucleotide, and a second oligonucleotide identical in sequence to the first oligonucleotide except that it dose not have modified nucleotide(s); and

(b) determining the stability and the degradation process of said first and second oligonucleotide in the biological sample by contacting the two oligonucleotides with the biological sample under identical conditions,

Whereby, where the first modified oligonucleotide is degraded less rapidly than the second oligonucleotide, the oligonucleotide with stability in a biological sample is identified.

By specifically modifying the UA/UA and/or CA/UG and/or UG/CA site(s) identified in an oligonucleotid, the invention achieves stabilizing the modified oligonucleotide by introducing only a relatively small amount chemically modified nucleotides into the oligonucleotide. Compared to randomly modified oligonucleotide in the art, the specific modification approach disclosed in the present invention greatly reduces the potential cytotoxicity and influence on the biological activity of the modified oligonucleotide.

Inventors of the present invention performed comprehensive investigation on the in vivo degradation of synthetic oligonucleotide, and found that replacing a relatively small amount of the nucleotides in UA/UA and/or CA/UG site(s) identified in a oligonucleotide sequence by corresponding chemically modified nucleotide(s) can greatly increase the stability of the modified oligonucleotide in biological samples, and at the same time, reduces the cytotoxicity caused by extensive and random modifications usually performed in the art, as well as the effects on biological activity.

The present invention is further illustrated using the following embodiments. Should be understood that the materials, methods, and examples described in the present invention are illustrative only and not intented to be limiting. Unless otherwise defined, all reagents and culture medium used in the invention are commercially available.

EXAMPLE 1 Synthesis of siRNA Oligonucleotides

siRNA oligonucleotides against target genes in table 1-182 were synthesized by Genepharma Ltd (Shanghai, China).

EXAMPLE 2 Assays of Serum Stability, Silencing Efficacy and Cytotoxicity of Variously Modified siRNA

Serum stability, silencing efficacy and cytotoxicity assay of modified and unmodified siRNAs in table 1-182 were tested using the methods of:

1. Serum Stability Assay

Serum degradation assays were performed at 37° C. by incubating 4 μL 20 μM modified or unmodified siRNA in 32 μL 1×PBS solution, containing 4 μL fetal bovine serum (Sigma). The final serum concentration was 10%. After serum treatment of 0, 3 or 6 hours, 10 μL reaction solution was removed and frozen immediately in liquid nitrogen to terminate the reaction. The samples were then stored at −80° C. until analysis.

Prepare a 20% polyacrylamide gel; mix 3 uL 3× loading buffer (30 mM EDTA, 36% glycerol, 0.06% bromophenol blue) with serum-treated siRNA sample; then load the sample into the gel and run electrophoresis at 80 mA under constant current condition. After electrophoresis, add 1× Sybr Gold (Invitrogen, Cat. 11494) into the sample and let it stain for 10 minutes before imaging and analysis. The results were presented in Table 1-182.

2. Silencing Efficacy Assay

Human embryonic kidney cells (HEK293) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin and 100 μg/ml streptomycin (Life Technologies, Gibco), and seeded into 24-well plates at a density of 1×10⁵ cells (0.5 mL culture medium/well). After 24 hours incubation and the cell density reached 50% confluence, the culture medium was changed to Opti-MEM (Gibco). Lipofectamine™ 2000 transfection reagent (Invitrogen) was used to co-transfect siRNA and reporter plasmids. Report vector (0.17 μg/well) carrying the target site of tested siRNA and firefly luciferase gene was transfected into the cells together with pRL-TK control vector carrying renilla luciferase gene. The final concentration of siRNA was 13 nM. Each siRNA was parallely transfected in three wells, with the same amount of the two reporter plasmids. The three wells without siRNA treatment were used as control. Four hours after transfection, the culture medium was changed to one milliliter DMEM growth medium (10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin and 100 μg/ml streptomycin). Twenty-four later, the cells were lysated by adding 10 uL cell lysis buffer, and the activity of both luciferases was measured with a fluorometer (Synergy HT, BioTek, USA), using Dual-Luciferase reporter assay system (Promega) according to the manufacturer's instructions. Silencing efficacy of the siRNA was calculated by the following formula, using siRNA-untreated cells as control. All the experiments were performed in triplicate and repeated for at least twice. The results were shown in table 1-182.

Silencing efficacy=(the expressional amount of firefly luciferase in test group/the expressional amount of renilla luciferase in test group)/(the expressional amount of firefly luciferase in control group/the expressional amount of renilla luciferase in control group)

3. Cytotoxicity Assay of Modified siRNA

Human embryonic kidney cells (HEK293) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin and 100 μg/ml streptomycin (Life Technologies, Gibco), and seeded into 24-well plates at a density of 1×10⁵ cells (0.5 mL culture medium/well). After 24 hours incubation and the cell density reached 50% confluence, the culture medium was changed to Opti-MEM (Gibco). Lipofectamine™ 2000 transfection reagent (Invitrogen) was used to transfect chemically synthetic siRNA into the cells at a final concentration of 13 nM. Each siRNA was parallely transfected in three independent wells, with three other siRNA-untreated wells as control. Four hours after transfection, the culture medium was changed to one milliliter DMEM growth medium (10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin and 100 μg/ml streptomycin).

Twenty-four later, removed the culture medium and washed the cells once with PBS. Add 1 mL PBS and 10 μL MTT into each well, incubate in a 5% CO₂ incubator at 37° C. for 4-6 hours; add 0.1 mL acidified isopropanol into each well, mix by vortexing; measure the absorbance value (A value) at 570 nm for each well, using a microplate reader. The growth inhibition ratio was calculated using the following formula, the results were shown in table 1-182.

Growth inhibition ratio(%)=(A value of test group−A value of control group)/A value of control group×100%

TABLE 1 Human KAZRIN (NM_201628) 718-738 BP (SEQ ID NO: 2) Locus Expression Growth Gene siRNA Stability inhibition ratio inhibition ratio 1-1 Unmodified siRNA + 84% 0% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-2A Random modification (2′-deoxy-2′-fluoro) ++ 27% 37% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-2B Random modification (2′-O-methyl) ++ 0% 32% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3A Specific modification (2′-O-methyl) ++ 27% 15% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3B Specific modification (2′-deoxy-2′fluoro) +++ 44% 12% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3C Specific modification (2′-O-methyl) ++ 56% 10% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3D Specific modification (2′-O-methyl) ++ 81% 11% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3E Specific modification (2′-O-methyl) +++ 49% 10% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3F Specific modification (2′-deoxy-2′-fluoro) ++ 49% 14% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3G Specific modification (2′-deoxy-2′-fluoro) ++ 85% 0% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3H Specific modification (2′-O-methyl) ++ 84% 6% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3I Specific modification (2′-O-methyl) ++ 23% 10% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3J Specific modification (2′-O-methyl) ++ 41% 14% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3K Specific modification (2′-deoxy-2′-fluoro) ++ 47% 15% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3L Specific modification (2′-O-methyl) ++ 83% 12% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3M Specific modification (2′-O-methyl) ++ 59% 7% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3N Specific modification (2′-deoxy-2′-fluoro) ++ 49% 0% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3O Specific modification (2′-O-methyl) ++ 85% 5% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3P Unmodified siRNA(hairpin, unmodified) +++ 85% 0% 5-AGCGCUUAAAGGGCGAGAAGAUUN UUUCGCGAAUUUCCCGCUCUUCUNNN 1-3Q Specific modification (hairpin, 2′-O-methyl) +++ 53% 10% 5-AGCGCUUAAAGGGCGAGAAGAUUN UUUCGCGAAUUUCCCGCUCUUCUNNN 1-3R Specific modification (discontiguous sense strand, +++ 78% 2% 2′-deoxy-2′-fluoro) 5-AGCGCUUAAAGG|GCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3S Specific modification (hybrid molecule, 2′-O-methyl) ++ 50% 7% 5-AGCGCUUAAAGGGCG(DA)GAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3T Specific modification (hybrid molecule, ++ 79% 9% 2′-deoxy-2′-fluoro) 5-AGCGCUUAAAGGGCG(DA)GAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3U Specific modification (phosphodiester bond +++ 45% 11% modification) 5-AGCGCUUAAAGGG-CGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5 1-3V Specific modification (2′-deoxy-2′-fluoro) +++ 51% 8% 5-AGCGCUUAAAGGGCGAGAAGAUU UUUCGCGAAUUUCCCGCUCUUCU-5

TABLE 2 Mouse (NM_008960.2) 1148-1166 BP (SEQ ID NO: 9) Locus Expression Growth inhibition Gene SIRNA Stability inhibition ratio ratio 2-1 Unmodified siRNA + 86% 0% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-2A Random modification (2′-O-methyl) ++ 15% 34% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-2B Random modification (2′-deoxy-2′-fluoro) ++ 37% 38% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3A Specific modification (2′-deoxy-2′-fluoro) ++ 57% 17% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3B Specific modification (2′-O-methyl) +++ 24% 34% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3C Specific modification (2′-O-methyl) +++ 51% 17% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3D Specific modification (2′-O-methyl) ++ 44% 37% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3E Specific modification (2′-O-methyl) +++ 7% 52% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3F Specific modification (2′-O-methyl) ++ 81% 14% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3G Specific modification (2′-O-methyl) +++ 32% 35% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3H Specific modification (2′-O-methyl) ++ 79% 6% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3I Specific modification (2′-O-methyl) ++ 51% 42% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3J Specific modification (2′-deoxy-2′-fluoro) ++ 75% 16% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3K Specific modification (2′-O-methyl) ++ 84% 4% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3L Specific modification (2′-O-methyl) ++ 81% 3% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3M Specific modification (2′-deoxy-2′-fluoro) +++ 54% 33% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3N Specific modification (2′-O-methyl) +++ 82% 5% 5-AACCCACCACAGCUAGAACUUNN UUGGGUGGUGUCGAUCUUGAANN 2-3O Specific modification (2′-deoxy-2′-fluoro) ++ 14% 23% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5 2-3P Unmodified siRNA (hairpin, unmodified) +++ 78% 5% 5-AACCCACCACAGCUAGAACUUNN UUGGGUGGUGUCGAUCUUGAANN 2-3Q Specific modification (hairpin, 2′-O-methyl) +++ 42% 34% 5-AACCCACCACAGCUAGAACUU UUGGGUGGUGUCGAUCUUGAA-5

TABLE 3 Human BIC (NR_001458.3) 289-310 BP (SEQ ID NO: 1) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 3-1 Unmodified siRNA + 88% 0% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-2A Random modification (2′-O-methyl) ++ 49% 41% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-2B Random modification (2′-deoxy-2′-fluoro) ++ 15% 37% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3A Specific modification (2′-O-methyl) +++ 80% 11% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3B Specific modification (2′-O-methyl) +++ 51% 31% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3C Specific modification (2′-deoxy-2′-fluoro) +++ 45% 57% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3D Specific modification (2′-deoxy-2′-fluoro) ++ 65% 32% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3E Specific modification (2′-O-methyl) ++ 75% 27% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3F Specific modification (2′-O-methyl) ++ 49% 48% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3G Specific modification (2′-O-methyl) ++ 23% 52% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3H Specific modification (2′-O-methyl) ++ 17% 42% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3I Specific modification (2′-deoxy-2′-fluoro) ++ 65% 21% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3J Specific modification (2′-O-methyl) ++ 17% 51% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3K Specific modification (2′-O-methyl) ++ 35% 48% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3L Specific modification (2′-deoxy-2′-fluoro) ++ 53% 45% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3M Specific modification (2′-deoxy-2′-fluoro) ++ 28% 39% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3N Specific modification (2′-O-methyl) +++ 8% 49% 5-UUAAUGCUAAUCGUGAUAGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3O Specific modification (2′-O-methyl) ++ 70% 9% 5-UUAAUGCUAAUCGUGA(DT)AGGGGUU AUAAUUACGAUUAGCACUAUCCCC-5 3-3P Specific modification (2′-O-methyl) ++ 72% 12% 5-UUAAUGCUAAUCGUGAAGG(DG)GUU AUAAUUACGAUUAGCACUAUCCCC-5

TABLE 4 745-763 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 4-1 unmodified ++ 83% 0% 5-AGAAGGACUACUAACCUCCTT TTUCUUCCUGAUGAUUGGAGG-5 4-2 Random modification (2′-O-methyl) ++ 49% 41% 5-AGAAGGACUACUAACCUCCTT TTUCUUCCUGAUGAUUGGAGG-5 4-3A Specific modification (2′-O-methyl) ++ 80% 15% 5-AGAAGGACUACUAACCUCCTT TTUCUUCCUGAUGAUUGGAGG-5 4-3B Specific modification (2′-O-methyl) +++ 81% 5% 5-AGAAGGACUACUAACCUCCTT TTUCUUCCUGAUGAUUGGAGG-5

TABLE 5 749-767 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 5-1 Unmodified siRNA + 69% 0% 5-GGACUACUAACCUCCAGUUTT TTCCUGAUGAUUGGAGGUCAA-5 5-2 Random modification (2′-O-methyl) ++ 7% 53% 5-GGACUACUAACCUCCAGUUTT TTCCUGAUGAUUGGAGGUCAA-5 5-3A Specific modification (2′-O-methyl) ++ 65% 21% 5-GGACUACUAACCUCCAGUUTT TTCCUGAUGAUUGGAGGUCAA-5 5-3B Specific modification (2′-O-methyl) +++ 69% 9% 5-GGAC UAC UAACCUCCAGUUTT TTCCUGAU GAU UGGAGGUCAA-5

TABLE 6 807-825 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 6-1 Unmodified siRNA + 69% 0% 5-GAAACUGGUACUUUCCCCCTT TTCUUUGACCAUGAAAGGGGG-5 6-2 Random modification (2′-deoxy-2′-fluoro) ++ 60% 37% 5-GAAACUGGUACUUUCCCCCTT TTCUUUGACCAUGAAAGGGGG-5 6-3A Specific modification (2′-deoxy-2′-fluoro) ++ 26% 12% 5-GAAACUGGUACUUUCCCCCTT TTCUUUGACCAU GAAAGGGGG-5 6-3B Specific modification (2′-deoxy-2′-fluoro) ++ 58% 8% 5-GAAACUGG UACUUUCCCCCTT TTCUUUGACCAU GAAAGGGGG-5

TABLE 7 818-836 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 7-1 Unmodified siRNA + 70% 0% 5-UUUCCCCCAGGUAACGAUUTT TTAAAGGGGGUCCAUUGCUAA-5 7-2 Random modification (2′-deoxy-2′-fluoro) ++ 68% 21% 5-UUUCCCCCAGGUAACGAUUTT TTAAAGGGGGUCCAUUGCUAA-5 7-3A Specific modification (2′-deoxy-2′-fluoro) ++ 78% 15% 5-UUUCCCCCAGG UA ACGAUUTT TTAAAGGGGGUCCAUUGCUAA-5 7-3B Specific modification (2′-deoxy-2′-fluoro) ++ 75% 8% 5-UUUCCCCCAGG UAACGAUUTT TTAAAGGGGGUCCAU UGCUAA-5

TABLE 8 822-840 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 8-1 Unmodified siRNA + 86% 0% 5-CCCCAGGUAACGAUUUUCUTT TTGGGGUCCAUUGCUAAAAGA-5 8-2 Random modification (2′-O-methyl) ++ 69% 53% 5-CCCCAGGUAACGAUUUUCUTT TTGGGGUCCAUUGCUAAAAGA-5 8-3A Specific modification (2′-O-methyl) ++ 79% 12% 5-CCCCAGGUAACGAUUUUCUTT TTGGGGUCCAUUGCUAAAAGA-5 8-3B Specific modification (2′-O-methyl) ++ 70% 5% 5-CCCCAGG UAACGAUUUUCUTT TTGGGGUCCAU UGCUAAAAGA-5

TABLE 9 889-907 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 9-1 Unmodified siRNA + 57% 0% 5-GGGAAACUGAAAGGCUAUGTT TTCCCUUUGACUUUCCGAUAC-5 9-2 Random modification (2′-deoxy-2′-fluoro) + 6% 47% 5-GGGAAACUGAAAGGCUAUGTT TTCCCUUUGACUUUCCGAUAC-5 9-3A Specific modification (2′-deoxy-2′-fluoro) ++ 51% 14% 5-GGGAAACUGAAAGGC UA UGTT TTCCCUUUGACUUUCCGAUAC-5 9-3B Specific modification (2′-deoxy-2′-fluoro) ++ 50% 4% 5-GGGAAACUGAAAGGC UAUGTT TTCCCUUUGACUUUCCGAUAC-5

TABLE 10 1084-1102 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 10-1 Unmodified siRNA + 97% 0% 5-GCGAGCAGAGAAUCUACCUTT TTCGCUCGUCUCUUAGAUGGA-5 10-2 Random modification (2′-O-methyl) ++ 65% 41% 5-GCGAGCAGAGAAUCUACCUTT TTCGCUCGUCUCUUAGAUGGA-5 103A Specific modification (2′-O-methyl) ++ 90% 9% 5-GCGAGCAGAGAAUC UACCUTT TTCGCUCGUCUCUUAGAU GGA-5 10-3B Specific modification (2′-O-methyl) ++ 90% 5% 5-GCGAGCAGAGAAUC UACCUTT TTCGCUCGUCUCUUAGAU GGA-5

TABLE 11 1088-1106 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 11-1 Unmodified siRNA + 79% 0% 5-GCAGAGAAUCUACCUUUCCTT TTCGUCUCUUAGAUGGAAAGG-5 11-2 Random modification (2′-O-methyl) ++ 13% 38% 5-GCAGAGAAUCUACCUUUCCTT TTCGUCUCUUAGAUGGAAAGG-5 11-3A Specific modification (2′-O-methyl) +++ 65% 12% 5-GCAGAGAAUCUACCUUUCCTT TTCGUCUCUUAGAUGGAAAGG-5 11-3B Specific modification (2′-O-methyl) ++ 75% 5% 5-G CAGAGAAUC UACCUUUCCTT TTCGU CUCUUAGAU GGAAAGG-5

TABLE 12 1099-1117 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 12-1 Unmodified siRNA + 84% 0% 5-ACCUUUCCACUUCUAAGCCTT TTUGGAAAGGUGAAGAUUCGG-5 12-2 Random modification (2′-O-methyl) ++ 75% 41% 5-ACCUUUCCACUUCUAAGCCTT TTUGGAAAGGUGAAGAUUCGG-5 12-3A Specific modification (2′-O-methyl) ++ 80% 15% 5-ACCUUUCCACUUCUAAGCCTT TTUGGAAAGGUGAAGAU UCGG-5 12-3B Specific modification (2′-O-methyl) ++ 75% 6% 5-ACCUUUCCACUUC UAAGCCTT TTUGGAAAGGUGAAGAU UCGG-5

TABLE 13 1111-1129 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 13-1 Unmodified siRNA + 90% 0% 5-CUAAGCCUGUUUCUUCCUCTT TTGAUUCGGACAAAGAAGGAG-5 13-2 Random modification (2′-deoxy-2′-fluoro) ++ 75% 57% 5-CUAAGCCUGUUUCUUCCUCTT TTGAUUCGGACAAAGAAGGAG-5 13-3A Specific modification (2′-deoxy-2′-fluoro) ++ 85% 12% 5-CUA AGCCUGUUUCUUCCUCTT TTGAU UCGGACAAAGAAGGAG-5 13-3B Specific modification (2′-deoxy-2′-fluoro) ++ 82% 4% 5-C UAAGCCUGUUUCUUCCUCTT TTGAUUCGGACAAAGAAGGAG-5

TABLE 14 2456-2474 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 14-1 Unmodified siRNA + 55% 0% 5-GAAGAUAGGAAGGGGCUUCTT TTCUUCUAUCCUUCCCCGAAG-5 14-2 Random modification (2′-deoxy-2′-fluoro) ++ 5% 23% 5-GAAGAUAGGAAGGGGCUUCTT TTCUUCUAUCCUUCCCCGAAG-5 14-3A Specific modification (2′-deoxy-2′-fluoro) ++ 45% 9% 5-GAAGAU AGGAAGGGGCUUCTT TTCUUCUAUCCUUCCCCGAAG-5 14-3B Specific modification (2′-deoxy-2′-fluoro) ++ 56% 4% 5-GAAGA UAGGAAGGGGCUUCTT TTCUUCUAU CCUUCCCCGAAG-5

TABLE 15 294-312 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 15-1 Unmodified siRNA + 73% 0% 5-AAUAAGCAGCUCGCGCUCCTT TTUUAUUCGUCGAGCGCGAGG-5 15-2 Random modification (2′-O-methyl) ++ 64% 23% 5-AAUAAGCAGCUCGCGCUCCTT TTUUAUUCGUCGAGCGCGAGG-5 15-3A Specific modification (2′-O-methyl) ++ 68% 12% 5-AA UAAGCAGCUCGCGCUCCTT TTUUAU UCGUCGAGCGCGAGG-5 15-3B Specific modification (2′-O-methyl) ++ 69% 4% 5-AA UAAGCAGCUCGCGCUCCTT TTUUAU UCGUCGAGCGCGAGG-5

TABLE 16 673-691 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 16-1 Unmodified siRNA + 93% 0% 5-UAGCCAGAGCCAAAGAAGCTT TTAUCGGUCUCGGUUUCUUCG-5 16-2 Random modification (2′-O-methyl) ++ 75% 57% 5-UAGCCAGAGCCAAAGAAGCTT TTAUCGGUCUCGGUUUCUUCG-5 16-3A Specific modification (2′-O-methyl) ++ 85% 12% 5- UAGCCAGAGCCAAAGAAGCTT TTAU CGGUCUCGGUUUCUUCG-5 16-3B Specific modification (2′-O-methyl) ++ 82% 4% 5- UAGCCAGAGCCAAAGAAGCTT TTAU CGGUCUCGGUUUCUUCG-5

TABLE 17 1012-1030 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 17-1 Unmodified siRNA + 49% 0% 5-AACAGUCCUUAGCUACGCUTT TTUUGUCAGGAAUCGAUGCGA-5 17-2 Random modification (2′-O-methyl) + 35% 57% 5-AACAGUCCUUAGCUACGCUTT TTUUGUCAGGAAUCGAUGCGA-5 17-3A Specific modification (2′-O-methyl) ++ 85% 12% 5-AACAGUCCU UAGC UACGCUTT TTUUGUCAGGAAU CGAU GCGA-5 17-3B Specific modification (2′-O-methyl) ++ 82% 4% 5-AACAGUCCU UAGC UACGCUTT TTUUGUCAGGAAUCGAU GCGA-5

TABLE 18 1383-1401 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 18-1 Unmodified siRNA + 72% 0% 5-CUAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5 18-2 Random modification (2′-deoxy-2′-fluoro) ++ 12% 42% 5-CUAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5 18-3A Specific modification (2′-deoxy-2′-fluoro) ++ 67% 12% 5-C UAGAGGAUCUUGAAGACCTT TTGAU CUCCUAGAACUUCUGG-5 18-3B Specific modification (2′-deoxy-2′-fluoro) ++ 82% 4% 5-CUA GAGGAUCUUGAAGACCTT TTGAU CUCCUAGAACUUCUGG-5

TABLE 19 2151-2169 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 19-1 Unmodified siRNA + 52% 0% 5-AUCGACCUGAAGGAGUACGTT TTUAGCUGGACUUCCUCAUGC-5 19-2 Random modification (2′-deoxy-2′-fluoro) ++ 21% 49% 5-AUCGACCUGAAGGAGUACGTT TTUAGCUGGACUUCCUCAUGC-5 19-3A Specific modification (2′-deoxy-2′-fluoro) ++ 46% 9% 5-AUCGACCUGAAGGAG UACGTT TTUAGCUGGACUUCCUCAU GC-5 19-3B Specific modification (2′-deoxy-2′-fluoro) ++ 82% 4% 5-AUCGACCUGAAGGAG UACGTT TTUAGCUGGACUUCCUC AUGC-5

TABLE 20 2459-2477 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 20-1 Unmodified siRNA + 53% 0% 5-GAUAGGAAGGGGCUUCAGCTT TTCUAUCCUUCCCCGAAGUCG-5 20-2 Random modification (2′-O-methyl) ++ 12% 52% 5-GAUAGGAAGGGGCUUCAGCTT TTCUAUCCUUCCCCGAAGUCG-5 20-3A Specific modification (2′-O-methyl) ++ 42% 16% 5-GA UAGGAAGGGGCUUCAGCTT TTCUAU CCUUCCCCGAAGUCG-5 20-3B Specific modification (2′-O-methyl) ++ 41% 6% 5-GA UAGGAAGGGGCUUCAGCTT TTCU AU CCUUCCCCGAAGUCG-5

TABLE 21 2935-2953 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 21-1 Unmodified siRNA + 72% 0% 5-AGUCCCUGGAGCCUUAAACTT TTUCAGGGACCUCGGAAUUUG-5 21-2 Random modification (2′-O-methyl) + 68% 41% 5-AGUCCCUGGAGCCUUAAACTT TTUCAGGGACCUCGGAAUUUG-5 21-3A Specific modification (2′-O-methyl) ++ 65% 12% 5-AGUCCCUGGAGCCU UAAACTT TTUCAGGGACCUCGGAAU UUG-5 21-3B Specific modification (2′-O-methyl) ++ 62% 5% 5-AGUCCCUGGAGCCU UA AACTT TTUCAGGGACCUCGGA AUUUG-5

TABLE 22 3327-3345 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 22-1 Unmodified siRNA + 39% 0% 5-AGCCACAUUUCUAGGAGAUTT TTUCGGUGUAAAGAUCCUCUA-5 22-2 Random modification (2′-O-methyl) ++ 19% 52% 5-AGCCACAUUUCUAGGAGAUTT TTUCGGUGUAAAGAUCCUCUA-5 22-3A Specific modification (2′-O-methyl) ++ 26% 16% 5-AGCCACAUUUC UAGGAGAUTT TTUCGGUGUAAAGAU CCUCUA-5 22-3B Specific modification (2′-O-methyl) ++ 29% 4% 5-AGCCACAUUUCUA GGAGAUTT TTUCGGUGUAAAGAUCCUCUA-5

TABLE 23 3449-3467 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 23-1 Unmodified siRNA + 73% 0% 5-GAUUCCAAACCCCACUAUCTT TTCUAAGGUUUGGGGUGAUAG-5 23-2 Random modification (2′-O-methyl) ++ 54% 57% 5-GAUUCCAAACCCCACUAUCTT TTCUAAGGUUUGGGGUGAUAG-5 23-3A Specific modification (2′-O-methyl) ++ 67% 13% 5-GAUUCCAAACCCCAC UAUCTT TTCUAAGGUUUGGGGUGAUAG-5 23-3B Specific modification (2′-O-methyl) ++ 69% 5% 5-GAUUCCAAACCCCAC UAUCTT TTCUAAGGUUUGGGGUG AUAG-5

TABLE 24 3751-3769 BP human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 24-1 Unmodified siRNA + 53% 0% 5-GAUACUUCUGGUUCCCUCCTT TTCUAUGAAGACCAAGGGAGG-5 24-2 Random modification (2′-O-methyl) ++ 45% 60% 5-GAUACUUCUGGUUCCCUCCTT TTCUAUGAAGACCAAGGGAGG-5 24-3A Specific modification (2′-O-methyl) ++ 45% 10% 5-GA UACUUCUGGUUCCCUCCTT TTCUAU GAAGACCAAGGGAGG-5 24-3B Specific modification (2′-O-methyl) ++ 46% 5% 5-GA UACUUCUGGUUCCCUCCTT TTCUAU GAAGACCAAGGGAGG-5

TABLE 25 5508-5526 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 25-1 Unmodified siRNA + 83% 0% 5-AGAGAAGGGCGUCUCUACATT TTUCUCUUCCCGCAGAGAUGU-5 25-2 Random modification (2′-deoxy-2′-fluoro) ++ 75% 49% 5-AGAGAAGGGCGUCUCUACATT TTUCUCUUCCCGCAGAGAUGU-5 25-3A Specific modification (2′-deoxy-2′-fluoro) ++ 71% 16% 5-AGAGAAGGGCGUCUC UA CATT TTUCUCUUCCCGCAGAGAU GU-5 25-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 4% 5-AGAGAAGGGCGUCUCUA CATT TTUCUCUUCCCGCAGAGAU GU-5

TABLE 26 5939-5957 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 26-1 Unmodified siRNA + 90% 0% 5-AGUUUCUAGGGCCGUGGCCTT TTUCAAAGAUCCCGGCACCGG-5 26-2 Random modification (2′-deoxy-2′-fluoro) ++ 75% 61% 5-AGUUUCUAGGGCCGUGGCCTT TTUCAAAGAUCCCGGCACCGG-5 26-3A Specific modification (2′-deoxy-2′-fluoro) ++ 85% 13% 5-AGUUUC UAGGGCCGUGGCCTT TTUCAAAGAU CCCGGCACCGG-5 26-3B Specific modification (2′-deoxy-2′-fluoro) ++ 82% 7% 5-AGUUUC UA GGGCCGUGGCCTT TTUCAAAGAU CCCGGCACCGG-5

TABLE 27 587-605 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 27-1 Unmodified siRNA + 62% 0% 5-GAAGAGUUAACCCGGGACUTT TTCUUCUCAAUUGGGCCCUGA-5 27-2 Random modification (2′-O-methyl) ++ 17% 61% 5-GAAGAGUUAACCCGGGACUTT TTCUUCUCAAUUGGGCCCUGA-5 27-3A Specific modification (2′-O-methyl) ++ 47% 13% 5-GAAGAGU UAACCCGGGACUTT TTCUUCUCAAU UGGGCCCUGA-5 27-3B Specific modification (2′-O-methyl) ++ 51% 6% 5-GAAGAGU UAACCCGGGACUTT TTCUUCUCAAU UGGGCCCUGA-5

TABLE 28 808-826 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 28-1 Unmodified siRNA + 95% 0% 5-CCGCCCGGCGGCGCCUUUATT TTGGCGGGCCGCCGCGGAAAU-5 28-2 Random modification (2′-O-methyl) ++ 49% 52% 5-CCGCCCGGCGGCGCCUUUATT TTGGCGGGCCGCCGCGGAAAU-5 28-3A Specific modification (2′-O-methyl) ++ 85% 11% 5-CCGCCCGGCGGCGCCUU UA TT TTGGCGGGCCGCCGCGGAA AU -5 28-3B Specific modification (2′-O-methyl) ++ 82% 4% 5-CCGCCCGGCGGCGCCUUUA TT TTGGCGGGCCGCCGCGGAA AU -5

TABLE 29 941-959 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 29-1 Unmodified siRNA + 73% 0% 5-ACCGACGAUUCUUCUACUCTT TTUGGCUGCUAAGAAGAUGAG-5 29-2 Random modification (2′-O-methyl) ++ 42% 47% 5-ACCGACGAUUCUUCUACUCTT TTUGGCUGCUAAGAAGAUGAG-5 29-3A Specific modification (2′-O-methyl) ++ 67% 9% 5-ACCGACGAUUCUUC UACUCTT TTUGGCUGCUAAGAAGAU GAG-5 29-3B Specific modification (2′-O-methyl) ++ 68% 4% 5-ACCGACGAUUCUUCUACUCTT TTUGGCUGCUAAGAAGAU GAG-5

TABLE 30 2262-2280 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 30-1 Unmodified siRNA + 54% 0% 5-GGUAGAAUAGGUUUUCCCCTT TTCCAUCUUAUCCAAAAGGGG-5 30-2 Random modification (2′-O-methyl) ++ 11% 71% 5-GGUAGAAUAGGUUUUCCCCTT TTCCAUCUUAUCCAAAAGGGG-5 30-3A Specific modification (2′-O-methyl) ++ 45% 10% 5-GG UA GAA UAGGUUUUCCCCTT TTCCAU CUUAU CCAAAAGGGG-5 30-3B Specific modification (2′-O-methyl) ++ 82% 3% 5-GG UAGAAUAGGUUUUCCCCTT TTCCAUCUUAU CCAAAAGGGG-5

TABLE 31 15-33 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 31-1 Unmodified siRNA + 58% 0% 5-UCCCUUCCACCGCCAUAUUTT TTAGGGAAGGUGGCGGUAUAA-5 31-2 Random modification (2′-O-methyl) ++ 11% 59% 5-UCCCUUCCACCGCCAUAUUTT TTAGGGAAGGUGGCGGUAUAA-5 31-3A Specific modification (2′-O-methyl) ++ 47% 13% 5-UCCCUUCCACCGCCA UAUUTT TTAGGGAAGGUGGCGGU AU AA-5 31-3B Specific modification (2′-O-methyl) ++ 49% 2% 5-UCCCUUCCACCGCCA UAUUTT TTAGGGAAGGUGGCGGUAU AA-5

TABLE 32 485-503 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 32-1 Unmodified siRNA + 70% 0% 5-CGAGUGUCUAACGGGAGCCTT TTGCUCACAGAUUGCCCUCGG-5 32-2 Random modification (2′-O-methyl) ++ 25% 56% 5-CGAGUGUCUAACGGGAGCCTT TTGCUCACAGAUUGCCCUCGG-5 32-3A Specific modification (2′-O-methyl) ++ 65% 9% 5-CGAGUGUC UAACGGGAGCCTT TTGCUCACAGAU UGCCCUCGG-5 32-3B Specific modification (2′-O-methyl) ++ 68% 2% 5-CGAGUGUCUAACGGGAGCCTT TTGCUCACAGAU UGCCCUCGG-5

TABLE 33 581-599 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 33-1 Unmodified siRNA + 91% 0% 5-GACCACGAAGAGUUAACCCTT TTCUGGUGCUUCUCAAUUGGG-5 33-2 Random modification (2′-deoxy-2′-fluoro) ++ 51% 59% 5-GACCACGAAGAGUUAACCCTT TTCUGGUGCUUCUCAAUUGGG-5 33-3A Specific modification (2′-deoxy-2′-fluoro) ++ 85% 13% 5-GACCACGAAGAGU UAACCCTT TTCUGGUGCUUCUCAAU UGGG-5 33-3B Specific modification (2′-deoxy-2′-fluoro) ++ 82% 7% 5-GACCACGAAGAGU UAACCCTT TTCUGGUGCUUCUCAAU UGGG-5

TABLE 34 591-609 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 34-1 Unmodified siRNA + 97% 0% 5-AGUUAACCCGGGACUUGGATT TTUCAAUUGGGCCCUGAACCU-5 34-2 Random modification (2′-deoxy-2′-fluoro) ++ 65% 57% 5-AGUUAACCCGGGACUUGGATT TTUCAAUUGGGCCCUGAACCU-5 34-3A Specific modification (2′-deoxy-2′-fluoro) ++ 85% 9% 5-AGU UAACCCGGGACUUGGATT TTUCAAU UGGGCCCUGAACCU-5 34-3B Specific modification (2′-deoxy-2′-fluoro) ++ 86% 4% 5-AGU UAACCCGGGACUUGGATT TTUCAAU UGGGCCCUGAACCU-5

TABLE 35 669-687 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 35-1 Unmodified siRNA + 35% 0% 5-AUCACAAACCCCUAGAGGGTT TTUAGUGUUUGGGGAUCUCCC-5 35-2 Random modification (2′-O-methyl) ++ 9% 51% 5-AUCACAAACCCCUAGAGGGTT TTUAGUGUUUGGGGAUCUCCC-5 35-3A Specific modification (2′-O-methyl) ++ 27% 10% 5-AUCACAAACCCC UAGAGGGTT TTUAGUGUUUGGGGAU CUCCC-5 35-3B Specific modification (2′-O-methyl) ++ 29% 4% 5-AUCACAAACCCC UAGAGGGTT TTUAGUGUUUGGGGAU CUCCC-5

TABLE 36 674-692 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 36-1 Unmodified siRNA + 81% 0% 5-AAACCCCUAGAGGGCAAGUTT TTUUUGGGGAUCUCCCGUUCA-5 36-2 Random modification (2′-O-methyl) ++ 62% 54% 5-AAACCCCUAGAGGGCAAGUTT TTUUUGGGGAUCUCCCGUUCA-5 36-3A Specific modification (2′-O-methyl) ++ 78% 11% 5-AAACCCC UAGAGGGCAAGUTT TTUUUGGGGAU CUCCCGUUCA-5 36-3B Specific modification (2′-O-methyl) ++ 75% 5% 5-AAACCCC UAGAGGGCAAGUTT TTUUUGGGGAU CUCCCGUUCA-5

TABLE 37 835-853 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 37-1 Unmodified siRNA + 95% 0% 5-UCCGGCUAACUCUGAGGACTT TTAGGCCGAUUGAGACUCCUG-5 37-2 Random modification (2′-deoxy-2′-fluoro) ++ 41% 61% 5-UCCGGCUAACUCUGAGGACTT TTAGGCCGAUUGAGACUCCUG-5 37-3A Specific modification (2′-deoxy-2′-fluoro) ++ 85% 9% 5-UCCGGC UAACUCUGAGGACTT TTAGGCCGAU UGAGACUCCUG-5 37-3B Specific modification (2′-deoxy-2′-fluoro) ++ 82% 3% 5-UCCGGC UAACUCUGAGGACTT TTAGGCCGAU UGAGACUCCUG-5

TABLE 38 943-961 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 38-1 Unmodified siRNA + 72% 0% 5-CGACGAUUCUUCUACUCAATT TTGCUGCUAAGAAGAUGAGUU-5 38-2 Random modification (2′-deoxy-2′-fluoro) ++ 56% 34% 5-CGACGAUUCUUCUACUCAATT TTGCUGCUAAGAAGAUGAGUU-5 38-3A Specific modification (2′-deoxy-2′-fluoro) ++ 62% 9% 5-CGACGAUUCUUC UACUCAATT TTGCUGCUAAGAAGAU GAGUU-5 38-3B Specific modification (2′-deoxy-2′-fluoro) ++ 67% 4% 5-CGACGAUUCUUC UACUCAATT TTGCUGCUAAGAAGAU GAGUU-5

TABLE 39 1353-1371 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 39-1 Unmodified siRNA + 73% 0% 5-UAAACUUUGGGGAAGGGAGTT TTAUUUGAAACCCCUUCCCUC-5 39-2 Random modification (2′-O-methyl) ++ 34% 48% 5-UAAACUUUGGGGAAGGGAGTT TTAUUUGAAACCCCUUCCCUC-5 39-3A Specific modification (2′-O-methyl) ++ 67% 11% 5- UAAACUUUGGGGAAGGGAGTT TTAU UUGAAACCCCUUCCCUC-5 39-3B Specific modification (2′-O-methyl) ++ 72% 3% 5- UAAACUUUGGGGAAGGGAGTT TTAU UUGAAACCCCUUCCCUC-5

TABLE 40 1401-1419 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 40-1 Unmodified siRNA + 95% 0% 5-AGCGGGGUAUGAAGAGCUUTT TTUCGCCCCAUACUUCUCGAA-5 40-2 Random modification (2′-O-methyl) ++ 75% 38% 5-AGCGGGGUAUGAAGAGCUUTT TTUCGCCCCAUACUUCUCGAA-5 40-3A Specific modification (2′-O-methyl) ++ 85% 13% 5-AGCGGGG UA UGAAGAGCUUTT TTUCGCCCCAU ACUUCUCGAA-5 40-3B Specific modification (2′-O-methyl) ++ 82% 6% 5-AGCGGGG UAUGAAGAGCUUTT TTUCGCCCCAU ACUUCUCGAA-5

TABLE 41 1711-1729 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth inhibition gene SIRNA Stability inhibition ratio ratio 41-1 Unmodified siRNA + 72% 0% 5-CUCCCCAGUCUCUCUUAAATT TTGAGGGGUCAGAGAGAAUUU-5 41-2 Random modification (2′-O-methyl) ++ 51% 46% 5-CUCCCCAGUCUCUCUUAAATT TTGAGGGGUCAGAGAGAAUUU-5 41-3A Specific modification (2′-O-methyl) ++ 68% 15% 5-CUCCCCAGUCUCUCU UAAATT TTGAGGGGUCAGAGAGAAU UU-5 41-3B Specific modification (2′-O-methyl) ++ 69% 7% 5-CUCCCCAGUCUCUCUUA AATT TTGAGGGGUCAGAGAGA AUUU-5

TABLE 42 108-126 BP chimpanzee SOD2 (NM_001009022) (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 42-1 Unmodified siRNA + 59% 0% 5-GAAUAACCUGAACGUCACCTT TTCUUAUUGGACUUGCAGUGG-5 42-2 Random modification (2′-O-methyl) ++ 17% 49% 5-GAAUAACCUGAACGUCACCTT TTCUUAUUGGACUUGCAGUGG-5 42-3A Specific modification (2′-O-methyl) ++ 51% 12% 5-GAA UAACCUGAACGUCACCTT TTCUUAU UGGACUUGCAGUGG-5 42-3B Specific modification (2′-O-methyl) ++ 55% 4% 5-GAA UAACCUGAACGUCACCTT TTCUUAU UGGACUUGCAGUGG-5

TABLE 43 119-137 BP Chimpanzee SOD2 (NM_001009022) (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 43-1 Unmodified siRNA + 65% 0% 5-ACGUCACCGAGGAGAAGUATT TTUGCAGUGGCUCCUCUUCAU-5 43-2 Random modification (2′-O-methyl) ++ 36% 46% 5-ACGUCACCGAGGAGAAGUATT TTUGCAGUGGCUCCUCUUCAU-5 43-3A Specific modification (2′-O-methyl) ++ 48% 8% 5-ACGUCACCGAGGAGAAG UATT TTUGCAGUGGCUCCUCUUCAU-5 43-3B Specific modification (2′-O-methyl) ++ 69% 2% 5-ACGUCACCGAGGAGAAG UATT TTUGCAGUGGCUCCUCUUCAU-5

TABLE 44 131-149 BP Chimpanzee SOD2 (NM_001009022) (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 44-1 Unmodified siRNA + 75% 0% 5-AGAAGUACCAGGAGGCGUUTT TTUCUUCAUGGUCCUCCGCAA-5 44-2 Random modification (2′-O-methyl) ++ 24% 39% 5-AGAAGUACCAGGAGGCGUUTT TTUCUUCAUGGUCCUCCGCAA-5 44-3A Specific modification (2′-O-methyl) ++ 68% 9% 5-AGAAG UACCAGGAGGCGUUTT TTUCUUCAU GGUCCUCCGCAA-5 44-3B Specific modification (2′-O-methyl) ++ 69% 3% 5-AGAAG UACCAGGAGGCGUUTT TTUCUUCAU GGUCCUCCGCAA-5

TABLE 45 168-186 BP Chimpanzee SOD2 (NM_001009022) (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 45-1 Unmodified siRNA + 72% 0% 5-AGCCCAGAUAGCUCUUCAGTT TTUCGGGUCUAUCGAGAAGUC-5 45-2 Random modification (2′-deoxy-2′-fluoro) ++ 35% 46% 5-AGCCCAGAUAGCUCUUCAGTT TTUCGGGUCUAUCGAGAAGUC-5 45-3A Specific modification (2′-deoxy-2′-fluoro) ++ 61% 12% 5-AGCCCAGA UAGCUCUUCAGTT TTUCGGGUCUAU CGAGAAGUC-5 45-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 5% 5-AGCCCAGA UAGCUCUUCAGTT TTUCGGGUCUAU CGAGAAGUC-5

TABLE 46 240-258 BP Chimpanzee SOD2 (NM_001009022) (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 46-1 Unmodified siRNA + 94% 0% 5-AAACCUCAGCCCUAACGGUTT TTUUUGGAGUCGGGAUUGCCA-5 46-2 Random modification (2′-O-methyl) ++ 51% 62% 5-AAACCUCAGCCCUAACGGUTT TTUUUGGAGUCGGGAUUGCCA-5 46-3A Specific modification (2′-O-methyl) ++ 79% 10% 5-AAACCUCAGCCC UAACGGUTT TTUUUGGAGUCGGGAU UGCCA-5 46-3B Specific modification (2′-O-methyl) ++ 69% 6% 5-AAACCUCAGCCC UA ACGGUTT TTUUUGGAGUCGGGAU UGCCA-5

TABLE 47 323-341 BP Chimpanzee SOD2 (NM_001009022) (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 47-1 Unmodified siRNA + 73% 0% 5-UUAAGGAGAAGCUGACGGCTT TTAAUUCCUCUUCGACUGCCG-5 47-2 Random modification (2′-O-methyl) ++ 24% 35% 5-UUAAGGAGAAGCUGACGGCTT TTAAUUCCUCUUCGACUGCCG-5 47-3A Specific modification (2′-O-methyl) ++ 67% 12% 5-U UAAGGAGAAGCUGACGGCTT TTAAU UCCUCUUCGACUGCCG-5 47-3B Specific modification (2′-O-methyl) ++ 69% 3% 5-U UAAGGAGAAGCUGACGGCTT TTAAU UCCUCUUCGACUGCCG-5

TABLE 48 391-409 BP Chimpanzee SOD2 (NM_001009022) Locus Expression Growth gene (SEQ ID NO: 4) SIRNA Stability inhibition ratio inhibition ratio 48-1 Unmodified siRNA + 44% 0% 5-AAGGAACGGGGACACUUACTT TTUUCCUUGCCCCUGUGAAUG-5 48-2 Random modification (2′-O-methyl) ++ 12% 46% 5-AAGGAACGGGGACACUUACTT TTUUCCUUGCCCCUGUGAAUG-5 48-3A Specific modification (2′-O-methyl) ++ 35% 15% 5-AAGGAACGGGGACACU UACTT TTUUCCUUGCCCCUGUGAAU G-5 48-3B Specific modification (2′-O-methyl) ++ 38% 6% 5-AAGGAACGGGGACACUUACTT TTUUCCUUGCCCCUGUGAAU G-5

TABLE 49 486-504 BP Chimpanzee SOD2 (NM_001009022) Locus Expression Growth gene (SEQ ID NO: 4) SIRNA Stability inhibition ratio inhibition ratio 49-1 Unmodified siRNA + 77% 0% 5-GGAGCACGCUUACUACCUUTT TTCCUCGUGCGAAUGAUGGAA-5 49-2 Random modification (2′-O-methyl) ++ 51% 38% 5-GGAGCACGCUUACUACCUUTT TTCCUCGUGCGAAUGAUGGAA-5 49-3A Specific modification (2′-O-methyl) ++ 68% 13% 5-GGAGCACGCU UAC UACCUUTT TTCCUCGUGCGAAU GAU GGAA-5 49-3B Specific modification (2′-O-methyl) ++ 69% 7% 5-GGAGCACGCU UAC UACCUUTT TTCCUCGUGCGAAU GAU GGAA-5

TABLE 50 168-186 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 50-1 Unmodified siRNA + 77% 0% 5-GGCGGGCUCUUUCCUAUUCTT TTCCGCCCGAGAAAGGAUAAG-5 50-2 Random modification (2′-O-methyl) ++ 51% 43% 5-GGCGGGCUCUUUCCUAUUCTT TTCCGCCCGAGAAAGGAUAAG-5 50-3A Specific modification (2′-O-methyl) ++ 68% 8% 5-GGCGGGCUCUUUCC UAUUCTT TTCCGCCCGAGAAAGGAU AAG-5 50-3B Specific modification (2′-O-methyl) ++ 69% 5% 5-GGCGGGCUCUUUCC UAUUCTT TTCCGCCCGAGAAAGGAU AAG-5

TABLE 51 2006-2024 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 51-1 Unmodified siRNA + 80% 0% 5-CCGAGAGCUCUCCUACCUUTT TTGGCUCUCGAGAGGAUGGAA-5 51-2 Random modification (2′-O-methyl) ++ 34% 43% 5-CCGAGAGCUCUCCUACCUUTT TTGGCUCUCGAGAGGAUGGAA-5 51-3A Specific modification (2′-O-methyl) ++ 72% 12% 5-CCGAGAGCUCUCC UACCUUTT TTGGCUCUCGAGAGGAU GGAA-5 51-3B Specific modification (2′-O-methyl) ++ 75% 5% 5-CCGAGAGCUCUCC UACCUUTT TTGGCUCUCGAGAGGAU GGAA-5

TABLE 52 2013-2031 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 52-1 Unmodified siRNA + 83% 0% 5-CUCUCCUACCUUCUCCUCUTT TTGAGAGGAUGGAAGAGGAGA-5 52-2 Random modification (2′-deoxy-2′-fluoro) ++ 69% 37% 5-CUCUCCUACCUUCUCCUCUTT TTGAGAGGAUGGAAGAGGAGA-5 52-3A Specific modification (2′-deoxy-2′-fluoro) ++ 73% 6% 5-CUCUCC UACCUUCUCCUCUTT TTGAGAGGAU GGAAGAGGAGA-5 52-3B Specific modification (2′-deoxy-2′-fluoro) ++ 78% 1% 5-CUCUCCUA CCUUCUCCUCUTT TTGAGAGGAUGGAAGAGGAGA-5

TABLE 53 2018-2036 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 53-1 Unmodified siRNA + 75% 0% 5-CUACCUUCUCCUCUUCUCCTT TTGAUGGAAGAGGAGAAGAGG-5 53-2 Random modification (2′-O-methyl) ++ 27% 38% 5-CUACCUUCUCCUCUUCUCCTT TTGAUGGAAGAGGAGAAGAGG-5 53-3A Specific modification (2′-O-methyl) ++ 68% 5% 5-C UA CCUUCUCCUCUUCUCCTT TTG AU GGAAGAGGAGAAGAGG-5 53-3B Specific modification (2′-O-methyl) ++ 69% 2% 5-C UACCUUCUCCUCUUCUCCTT TTGAU GGAAGAGGAGAAGAGG-5

TABLE 54 13-31 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 54-1 Unmodified siRNA + 43% 0% 5-AGCCUCCAAACUCCUAGCUTT TTUCGGAGGUUUGAGGAUCGA-5 54-2 Random modification (2′-deoxy-2′-fluoro) ++ 16% 34% 5-AGCCUCCAAACUCCUAGCUTT TTUCGGAGGUUUGAGGAUCGA-5 54-3A Specific modification (2′-deoxy-2′-fluoro) ++ 32% 9% 5-AGCCUCCAAACUCC UAGCUTT TTUCGGAGGUUUGAGGAU CGA-5 54-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 3% 5-AGCCUCCAAACUCC UAGCUTT TTUCGGAGGUUUGAGGAU CGA-5

TABLE 55 24-42 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 55-1 Unmodified siRNA + 75% 0% 5-UCCUAGCUGUCUUGUCCCUTT TTAGGAUCGACAGAACAGGGA-5 55-2 Random modification (2′-O-methyl) ++ 27% 33% 5-UCCUAGCUGUCUUGUCCCUTT TTAGGAUCGACAGAACAGGGA-5 55-3A Specific modification (2′-O-methyl) ++ 68% 8% 5-UCC UAGCUGUCUUGUCCCUTT TTAGGAU CGACAGAACAGGGA-5 55-3B Specific modification (2′-O-methyl) ++ 71% 1% 5-UCC UAGCUGUCUUGUCCCUTT TTAGGAU CGACAGAACAGGGA-5

TABLE 56 162-180 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 56-1 Unmodified siRNA + 53% 0% 5-AUACUUGGCGGGCUCUUUCTT TTUAUGAACCGCCCGAGAAAG-5 56-2 Random modification (2′-O-methyl) ++ 19% 35% 5-AUACUUGGCGGGCUCUUUCTT TTUAUGAACCGCCCGAGAAAG-5 56-3A Specific modification (2′-O-methyl) ++ 42% 6% 5-A UACUUGGCGGGCUCUUUCTT TTUAU GAACCGCCCGAGAAAG-5 56-3B Specific modification (2′-O-methyl) ++ 48% 1% 5-A UACUUGGCGGGCUCUUUCTT TTUAUGAACCGCCCGAGAAAG-5

TABLE 57 536-554 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 57-1 Unmodified siRNA + 77% 0% 5-GGGGCUCUUCUACAUUCCCTT TTCCCCGAGAAGAUGUAAGGG-5 57-2 Random modification (2′-O-methyl) ++ 51% 34% 5-GGGGCUCUUCUACAUUCCCTT TTCCCCGAGAAGAUGUAAGGG-5 57-3A Specific modification (2′-O-methyl) ++ 68% 5% 5-GGGGCUCUUC UACAUUCCCTT TTCCCCGAGAAGAU GUAAGGG-5 57-3B Specific modification (2′-O-methyl) ++ 72% 2% 5-GGGGCUCUUCUA CAUUCCCTT TTCCCCGAGAAGAU GUAAGGG-5

TABLE 58 669-687 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 58-1 Unmodified siRNA + 87% 0% 5-GAGUAUUUCCGCUGGAACUTT TTCUCAUAAAGGCGACCUUGA-5 58-2 Random modification (2′-deoxy-2′-fluoro) ++ 21% 37% 5-GAGUAUUUCCGCUGGAACUTT TTCUCAUAAAGGCGACCUUGA-5 58-3A Specific modification (2′-deoxy-2′-fluoro) ++ 73% 6% 5-GAG UAUUUCCGCUGGAACUTT TTCUCAU AAAGGCGACCUUGA-5 58-3B Specific modification (2′-deoxy-2′-fluoro) ++ 75% 1% 5-GAG UAUUUCCGCUGGAACUTT TTCUCAU AAAGGCGACCUUGA-5

TABLE 59 753-771 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 59-1 Unmodified siRNA + 85% 0% 5-GCUGAGGAAAGGGACAUCUTT TTCGACUCCUUUCCCUGUAGA-5 59-2 Random modification (2′-O-methyl) ++ 61% 31% 5-GCUGAGGAAAGGGACAUCUTT TTCGACUCCUUUCCCUGUAGA-5 59-3A Specific modification (2′-O-methyl) ++ 76% 7% 5-GCUGAGGAAAGGGAC AUCUTT TTCGACUCCUUUCCCUG UAGA-5 59-3B Specific modification (2′-O-methyl) ++ 78% 3% 5-GCUGAGGAAAGGGACAUCUTT TTCGACUCCUUUCCCUG UA GA-5

TABLE 60 800-818 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 60-1 Unmodified siRNA + 75% 0% 5-GUACUCUGAUGAGGAAGAGTT TTCAUGAGACUACUCCUUCUC-5 60-2 Random modification (2′-O-methyl) ++ 18% 37% 5-GUACUCUGAUGAGGAAGAGTT TTCAUGAGACUACUCCUUCUC-5 60-3A Specific modification (2′-O-methyl) ++ 68% 8% 5-G UACUCUGAUGAGGAAGAGTT TTCAU GAGACUACUCCUUCUC-5 60-3B Specific modification (2′-O-methyl) ++ 69% 1% 5-G UACUCUGAUGAGGAAGAGTT TTCAUGAGACUACUCCUUCUC-5

TABLE 61 854-872 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 61-1 Unmodified siRNA + 93% 0% 5-GGCCAAAGUAAUCGUGGUUTT TTCCGGUUUCAUUAGCACCAA-5 61-2 Random modification (2′-O-methyl) ++ 37% 31% 5-GGCCAAAGUAAUCGUGGUUTT TTCCGGUUUCAUUAGCACCAA-5 61-3A Specific modification (2′-O-methyl) ++ 86% 10% 5-GGCCAAAG UAAUCGUGGUUTT TTCCGGUUUCAU UAGCACCAA-5 61-3B Specific modification (2′-O-methyl) ++ 85% 5% 5-GGCCAAAG UAAUCGUGGUUTT TTCCGGUUUCAU UAGCACCAA-5

TABLE 62 1602-1620 BP Rhesus monkey RECEPTOR (XM_001111972) Locus Expression Growth gene (SEQ ID NO: 5) SIRNA Stability inhibition ratio inhibition ratio 62-1 Unmodified siRNA + 81% 0% 5-GUCUAUGCCAAGAAGGGAGTT TTCAGAUACGGUUCUUCCCUC-5 62-2 Random modification (2′-O-methyl) ++ 24% 31% 5-GUCUAUGCCAAGAAGGGAGTT TTCAGAUACGGUUCUUCCCUC-5 62-3A Specific modification (2′-O-methyl) ++ 72% 7% 5-GUC UA UGCCAAGAAGGGAGTT TTCAGAU ACGGUUCUUCCCUC-5 62-3B Specific modification (2′-O-methyl) ++ 76% 2% 5-GUC UAUGCCAAGAAGGGAGTT TTCAGAU ACGGUUCUUCCCUC-5

TABLE 63 Rhesus monkey RECEPTOR (XM_001111972) 2293-2311 BP (SEQ ID NO: 5) Locus Expression inhibition Growth inhibition gene SIRNA Stability ratio ratio 63-1 Unmodified siRNA + 84% 0% 5-UCUACACCGCGCCCCCCUCTT TTAGAUGUGGCGCGGGGGGAG-5 63-2 Random modification (2′-O-methyl) ++ 39% 33% 5-UCUACACCGCGCCCCCCUCTT TTAGAUGUGGCGCGGGGGGAG-5 63-3A Specific modification (2′-O-methyl) ++ 73% 6% 5-UC UA CACCGCGCCCCCCUCTT TTAGAU GUGGCGCGGGGGGAG-5 63-3B Specific modification (2′-O-methyl) ++ 79% 3% 5-UC UACACCGCGCCCCCCUCTT TTAGAU GUGGCGCGGGGGGAG-5

TABLE 64 Rhesus monkey RECEPTOR (XM_001111972) 2302-2320 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 64-1 Unmodified siRNA + 81% 0% 5-CGCCCCCCUCAAGCUACCGTT TTGCGGGGGGAGUUCGAUGGC-5 64-2 Random modification (2′-O-methyl) ++ 44% 48% 5-CGCCCCCCUCAAGCUACCGTT TTGCGGGGGGAGUUCGAUGGC-5 64-3A Specific modification (2′-O-methyl) ++ 72% 9% 5-CGCCCCCCUCAAGC UACCGTT TTGCGGGGGGAGUUCGAU GGC-5 64-3B Specific modification (2′-O-methyl) ++ 76% 3% 5-CGCCCCCCUCAAGC UACCGTT TTGCGGGGGGAGUUCGAU GGC-5

TABLE 65 Rhesus monkey RECEPTOR (XM_001111972) 2314-2332 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 65-1 Unmodified siRNA + 47% 0% 5-GCUACCGCAACCACGAGCUTT TTCGAUGGCGUUGGUGCUCGA-5 65-2 Random modification (2′-deoxy-2′-fluoro) ++ 21% 37% 5-GCUACCGCAACCACGAGCUTT TTCGAUGGCGUUGGUGCUCGA-5 65-3A Specific modification (2′-deoxy-2′-fluoro) ++ 42% 7% 5-GC UACCGCAACCACGAGCUTT TTCGAU GGCGUUGGUGCUCGA-5 65-3B Specific modification (2′-deoxy-2′-fluoro) ++ 45% 3% 5-GC UACCGCAACCACGAGCUTT TTCGAU GGCGUUGGUGCUCGA-5

TABLE 66 Rhesus monkey RECEPTOR (XM_001111972) 2522-2540 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 66-1 Unmodified siRNA + 84% 0% 5-CUCCUUCAUUCCAGCCUAUTT TTGAGGAAGUAAGGUCGGAUA-5 66-2 Random modification (2′-O-methyl) ++ 51% 31% 5-CUCCUUCAUUCCAGCCUAUTT TTGAGGAAGUAAGGUCGGAUA-5 66-3A Specific modification (2′-O-methyl) ++ 78% 8% 5-CUCCUUCAUUCCAGCC UAUTT TTGAGGAAGUAAGGUCGGAU A-5 66-3B Specific modification (2′-O-methyl) ++ 81% 4% 5-CUCCUUCAUUCCAGCC UAUTT TTGAGGAAGUAAGGUCGGAU A-5

TABLE 67 Rhesus monkey RECEPTOR (XM_001111972) 2998-3016 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 67-1 Unmodified siRNA + 78% 0% 5-AGAAAAGCAGCGAUACGCUTT TTUCUUUUCGUCGCUAUGCGA-5 67-2 Random modification (2′-O-methyl) ++ 34% 37% 5-AGAAAAGCAGCGAUACGCUTT TTUCUUUUCGUCGCUAUGCGA-5 67-3A Specific modification (2′-O-methyl) ++ 68% 8% 5-AGAAAAGCAGCGA UACGCUTT TTUCUUUUCGUCGCUAUGCGA-5 67-3B Specific modification (2′-O-methyl) ++ 69% 1% 5-AGAAAAGCAGCGA UACGCUTT TTUCUUUUCGUCGCUAUGCGA-5

TABLE 68 Dog B cell lymphoma (NM_001003016) 480-498 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 68-1 Unmodified siRNA + 93% 0% 5-GGAGCUAGACGGGUACGAGTT TTCCUCGAUCUGCCCAUGCUC-5 68-2 Random modification (2′-O-methyl) ++ 75% 51% 5-GGAGCUAGACGGGUACGAGTT TTCCUCGAUCUGCCCAUGCUC-5 68-3A Specific modification (2′-O-methyl) ++ 82% 9% 5-GGAGC UAGACGGG UACGAGTT TTCCUCGAU CUGCCCAU GCUC-5 68-3B Specific modification (2′-O-methyl) ++ 81% 10% 5-GGAGC UA GACGGG UACGAGTT TTCCUCGAU CUGCCCAUGCUC-5

TABLE 69 dog B cell lymphoma (NM_001003016) 489-507 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 69-1 Unmodified siRNA ++ 70% 0% 5-CGGGUACGAGCCGGAACCUTT TTGCCCAUGCUCGGCCUUGGA-5 69-2 Random modification (2′-deoxy-2′-fluoro) +++ 61% 43% 5-CGGGUACGAGCCGGAACCUTT TTGCCCAUGCUCGGCCUUGGA-5 69-3A Specific modification (2′-deoxy-2′-fluoro) +++ 68% 8% 5-CGGG UA CGAGCCGGAACCUTT TTGCCCAU GCUCGGCCUUGGA-5 69-3B Specific modification (2′-deoxy-2′-fluoro) +++ 69% 1% 5-CGGGUACGAGCCGGAACCUTT TTGCCCAU GCUCGGCCUUGGA-5

TABLE 70 dog B cell lymphoma (NM_001003016) 578-596 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 70-1 Unmodified siRNA + 87% 0% 5-ACGGCUCGCUACCCUCGACTT TTUGCCGAGCGAUGGGAGCUG-5 70-2 Random modification (2′-deoxy-2′-fluoro) +++ 72% 37% 5-ACGGCUCGCUACCCUCGACTT TTUGCCGAGCGAUGGGAGCUG-5 70-3A Specific modification (2′-deoxy-2′-fluoro) +++ 78% 4% 5-ACGGCUCGC UACCCUCGACTT TTUGCCGAGCGAU GGGAGCUG-5 70-3B Specific modification (2′-deoxy-2′-fluoro) 5-ACGGCUCGCUA CCCUCGACTT +++ 83% 1% TTUGCCGAGCGAUGGGAGCUG-5

TABLE 71 dog B cell lymphoma (NM_001003016) 1071-1089 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 71-1 Unmodified siRNA + 97% 0% 5-AGAGGACCUAGAAGGCGGCTT TTUCUCCUGGAUCUUCCGCCG-5 71-2 Random modification (2′-O-methyl) ++ 72% 34% 5-AGAGGACCUAGAAGGCGGCTT TTUCUCCUGGAUCUUCCGCCG-5 71-3A Specific modification (2′-O-methyl) ++ 89% 4% 5-AGAGGACC UAGAAGGCGGCTT TTUCUCCUGGAU CUUCCGCCG-5 71-3B Specific modification (2′-O-methyl) ++ 92% 1% 5-AGAGGACCUA GAAGGCGGCTT TTUCUCCUGGAUCUUCCGCCG-5

TABLE 72 dog B cell lymphoma (NM_001003016) 21-39 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 72-1 Unmodified siRNA + 77% 0% 5-AACUCUACUGUGGAGUCGGTT TTUUGAGAUGACACCUCAGCC-5 72-2 Random modification (2′-O-methyl) +++ 57% 32% 5-AACUCUACUGUGGAGUCGGTT TTUUGAGAUGACACCUCAGCC-5 72-3A Specific modification (2′-O-methyl) +++ 68% 8% 5-AACUC UACUGUGGAGUCGGTT TTUUGAGAU GACACCUCAGCC-5 72-3B Specific modification (2′-O-methyl) +++ 69% 1% 5-AACUC UACUGUGGAGUCGGTT TTUUGAGAU GACACCUCAGCC-5

TABLE 73 dog B cell lymphoma (NM_001003016) 124-142 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 73-1 Unmodified siRNA + 86% 0% 5-AGAAACGCAGUAAUCCGGATT TTUCUUUGCGUCAUUAGGCCU-5 73-2 Random modification (2′-O-methyl) +++ 80% 43% 5-AGAAACGCAGUAAUCCGGATT TTUCUUUGCGUCAUUAGGCCU-5 73-3A Specific modification (2′-O-methyl) ++ 81% 6% 5-AGAAACGCAG UAAUCCGGATT TTUCUUUGCGUCAU UAGGCCU-5 73-3B Specific modification (2′-O-methyl) ++ 85% 1% 5-AGAAACGCAG UA AUCCGGATT TTUCUUUGCGUCAU UAGGCCU-5

TABLE 74 dogB cell lymphoma (NM_001003016) 132-150 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 74-1 Unmodified siRNA + 72% 0% 5-AGUAAUCCGGACUCAACUCTT TTUCAUUAGGCCUGAGUUGAG-5 74-2 Random modification (2′-deoxy-2′-fluoro) ++ 59% 17% 5-AGUAAUCCGGACUCAACUCTT TTUCAUUAGGCCUGAGUUGAG-5 74-3A Specific modification (2′-deoxy-2′-fluoro) ++ 68% 4% 5-AG UAAUCCGGACUCAACUCTT TTUCAU UAGGCCUGAGUUGAG-5 74-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 1% 5-AG UAAUCCGGACUCAACUCTT TTUCAU UAGGCCUGAGUUGAG-5

TABLE 75 dog B cell lymphoma (NM_001003016) 616-634 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 75-1 Unmodified siRNA + 81% 0% 5-GAGGAAGAUGAGUUGUACCTT TTCUCCUUCUACUCAACAUGG-5 75-2 Random modification (2′-O-methyl) ++ 70% 29% 5-GAGGAAGAUGAGUUGUACCTT TTCUCCUUCUACUCAACAUGG-5 75-3A Specific modification (2′-O-methyl) +++ 76% 7% 5-GAGGAAGA UGAGUUGUACCTT TTCUCCUUCUAC UCAACAUGG-5 75-3B Specific modification (2′-O-methyl) +++ 77% 2% 5-GAGGAAGA UGAGUUGUACCTT TTCUCCUUCUAC UCAACAUGG-5

TABLE 76 dog B cell lymphoma (NM_001003016) 993-1011 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 76-1 Unmodified siRNA + 62% 0% 5-AGAUGUUCUCGUAAGGACGTT TTUCUACAAGAGCAUUCCUGC-5 76-2 Random modification (2′-O-methyl) +++ 53% 17% 5-AGAUGUUCUCGUAAGGACGTT TTUCUACAAGAGCAUUCCUGC-5 76-3A Specific modification (2′-O-methyl) +++ 60% 6% 5-AGAUGUUCUCG UAAGGACGTT TTUCUACAAGAGCAU UCCUGC-5 76-3B Specific modification (2′-O-methyl) +++ 69% 1% 5-AGAUGUUCUCGUAAGGACGTT TTUCUACAAGAGCAU UCCUGC-5

TABLE 77 dog B cell lymphoma (NM_001003016) 999-1017 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 77-1 Unmodified siRNA + 58% 0% 5-UCUCGUAAGGACGAAACGATT TTAGAGCAUUCCUGCUUUGCU-5 77-2 Random modification (2′-O-methyl) ++ 34% 21% 5-UCUCGUAAGGACGAAACGATT TTAGAGCAUUCCUGCUUUGCU-5 77-3A Specific modification (2′-O-methyl) ++ 52% 6% 5-UCUCG UA AGGACGAAACGATT TTAGAGCAU UCCUGCUUUGCU-5 77-3B Specific modification (2′-O-methyl) ++ 55% 0% 5-UCUCGUAAGGACGAAACGATT TTAGAGCAU UCCUGCUUUGCU-5

TABLE 78 dog B cell lymphoma(NM_001003016) 1268-1286 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 78-1 Unmodified siRNA ++ 71% 0% 5-GCUGUAACCUCGGAGAGUUTT TTCGACAUUGGAGCCUCUCAA-5 78-2 Random modification (2′-deoxy-2′-fluoro) +++ 51% 23% 5-GCUGUAACCUCGGAGAGUUTT TTCGACAUUGGAGCCUCUCAA-5 78-3A Specific modification (2′-deoxy-2′-fluoro) +++ 62% 4% 5-GCUG UAACCUCGGAGAGUUTT TTCGAC AU UGGAGCCUCUCAA-5 78-3B Specific modification (2′-deoxy-2′-fluoro) +++ 69% 1% 5-GCUG UAACCUCGGAGAGUUTT TTCGACAU UGGAGCCUCUCAA-5

TABLE 79 dog B cell lymphoma(NM_001003016) 1275-1293 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 79-1 Unmodified siRNA + 87% 0% 5-CCUCGGAGAGUUCUACUCUTT TTGGAGCCUCUCAAGAUGAGA-5 79-2 Random modification (2′-O-methyl) ++ 34% 27% 5-CCUCGGAGAGUUCUACUCUTT TTGGAGCCUCUCAAGAUGAGA-5 79-3A Specific modification (2′-O-methyl) ++ 85% 3% 5-CCUCGGAGAGUUC UACUCUTT TTGGAGCCUCUCAAGAU GAGA-5 79-3B Specific modification (2′-O-methyl) ++ 85% 0% 5-CCUCGGAGAGUUCUACUCUTT TTGGAGCCUCUCAAGAU GAGA-5

TABLE 80 dog B cell lymphoma(NM_001003016) 1308-1326 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 80-1 Unmodified siRNA + 71% 0% 5-GCAAGUGGCAAGAGGAUUATT TTCGUUCACCGUUCUCCUAAU-5 80-2 Random modification (2′-O-methyl) ++ 55% 36% 5-GCAAGUGGCAAGAGGAUUATT TTCGUUCACCGUUCUCCUAAU-5 80-3A Specific modification (2′-O-methyl) ++ 68% 8% 5-GCAAGUGGCAAGAGGAU UATT TTCGUUCACCGUUCUCCUAAU -5 80-3B Specific modification (2′-O-methyl) ++ 69% 1% 5-GCAAGUGGCAAGAGGAU UATT TTCGUUCACCGUUCUCCUAAU -5

TABLE 81 dog B cell lymphoma(NM_001003016) 1347-1365 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 81-1 Unmodified siRNA + 86% 0% 5-AUGGGAGAAGUAGUCCCCCTT TTUACCCUCUUCAUCAGGGGG-5 81-2 Random modification (2′-O-methyl) +++ 71% 21% 5-AUGGGAGAAGUAGUCCCCCTT TTUACCCUCUUCAUCAGGGGG-5 81-3A Specific modification (2′-O-methyl) +++ 82% 4% 5-AUGGGAGAAG UAGUCCCCCTT TTUACCCUCUUCAU CAGGGGG-5 81-3B Specific modification (2′-O-methyl) +++ 84% 1% 5-AUGGGAGAAG UAGUCCCCCTT TTUACCCUCUUCAU CAGGGGG-5

TABLE 82 dog B cell lymphoma(NM_001003016) 1354-1372 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 82-1 Unmodified siRNA + 75% 0% 5-AAGUAGUCCCCCUUGAAGATT TTUUCAUCAGGGGGAACUUCU-5 82-2 Random modification (2′-deoxy-2′-fluoro) ++ 53% 27% 5-AAGUAGUCCCCCUUGAAGATT TTUUCAUCAGGGGGAACUUCU-5 82-3A Specific modification (2′-deoxy-2′-fluoro) ++ 64% 6% 5-AAG UAGUCCCCCUUGAAGATT TTUUCAU CAGGGGGAACUUCU-5 82-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 1% 5-AAGUA GUCCCCCUUGAAGATT TTUUCAU CAGGGGGAACUUCU-5

TABLE 83 dog B cell lymphoma(NM_001003016) 1461-1479 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 83-1 Unmodified siRNA + 97% 0% 5-GGUAGGGUUGAAGAGACUUTT TTCCAUCCCAACUUCUCUGAA-5 83-2 Random modification (2′-O-methyl) +++ 58% 27% 5-GGUAGGGUUGAAGAGACUUTT TTCCAUCCCAACUUCUCUGAA-5 83-3A Specific modification (2′-O-methyl) +++ 94% 3% 5-GG UAGGGUUGAAGAGACUUTT TTCCAU CCCAACUUCUCUGAA-5 83-3B Specific modification (2′-O-methyl) +++ 95% 0% 5-GGUAGGGUUGAAGAGACUUTT TTCCAU CCCAACUUCUCUGAA-5

TABLE 84 623-641 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 84-1 Unmodified siRNA ++ 86% 0% 5-AGCGCUUAAAGGGCGAGAAGATT TTUCGCGAAUUUCCCGCUCUUCU-5 84-2 Random modification (2′-O-methyl) +++ 49% 25% 5-AGCGCUUAAAGGGCGAGAAGATT TTUCGCGAAUUUCCCGCUCUUCU-5 84-3A Specific modification (2′-O-methyl) +++ 85% 7% 5-AGCGCU UAAAGGGCGAGAAGATT TTUCGCGAAU UUCCCGCUCUUCU-5 84-3B Specific modification (2′-O-methyl) 5-AGCGCU UAAAGGGCGAGAAGATT +++ 85% 1% TTUCGCGAAU UUCCCGCUCUUCU-5

TABLE 85 2541-2559 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 85-1 Unmodified siRNA + 91% 0% 5-GGCCUUUCUCUCUAGAUAUTT TTCCGGAAAGAGAGAUCUAUA-5 85-2 Random modification (2′-O-methyl) +++ 80% 31% 5-GGCCUUUCUCUCUAGAUAUTT TTCCGGAAAGAGAGAUCUAUA-5 85-3A Specific modification (2′-O-methyl) +++ 89% 5% 5-GGCCUUUCUCUC UAGA UAUTT TTCCGGAAAGAGAGAU CUAU A-5 85-3B Specific modification (2′-O-methyl) +++ 90% 1% 5-GGCCUUUCUCUCUAGAUAUTT TTCCGGAAAGAGAGAU CUAU A-5

TABLE 86 2785-2803 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 86-1 Unmodified siRNA + 49% 0% 5-GCCUCUCUAUCCUUAGCUUTT TTCGGAGAGAUAGGAAUCGAA-5 86-2 Random modification (2′-deoxy-2′-fluoro) +++ 34% 37% 5-GCCUCUCUAUCCUUAGCUUTT TTCGGAGAGAUAGGAAUCGAA-5 86-3A Specific modification (2′-deoxy-2′-fluoro) +++ 47% 6% 5-GCCUCUC UAUCCU UAGCUUTT TTCGGAGAGAU AGGAAU CGAA-5 86-3B Specific modification (2′-deoxy-2′-fluoro) +++ 48% 1% 5-GCCUCUCUAUCCUUAGCUUTT TTCGGAGAGAU AGGAAU CGAA-5

TABLE 87 487-505 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 87-1 Unmodified siRNA + 90% 0% 5-AAGGACCUAGAGGAGUCACTT TTUUCCUGGAUCUCCUCAGUG-5 87-2 Random modification (2′-deoxy-2′-fluoro) ++ 31% 25% 5-AAGGACCUAGAGGAGUCACTT TTUUCCUGGAUCUCCUCAGUG-5 87-3A Specific modification (2′-deoxy-2′-fluoro) ++ 87% 4% 5-AAGGACC UAGAGGAGUCACTT TTUUCCUGGAU CUCCUCAGUG-5 87-3B Specific modification (2′-deoxy-2′-fluoro) ++ 88% 1% 5-AAGGACC UAGAGGAGUCACTT TTUUCCUGGAU CUCCUCAGUG-5

TABLE 88 614-632 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 88-1 Unmodified siRNA + 87% 0% 5-CUGACCGGAAGCGCUUAAATT TTGACUGGCCUUCGCGAAUUU-5 88-2 Random modification (2′-O-methyl) +++ 27% 37% 5-CUGACCGGAAGCGCUUAAATT TTGACUGGCCUUCGCGAAUUU-5 88-3A Specific modification (2′-O-methyl) +++ 85% 5% 5-CUGACCGGAAGCGCU UAAATT TTGACUGGCCUUCGCGAAU UU-5 88-3B Specific modification (2′-O-methyl) +++ 86% 1% 5-CUGACCGGAAGCGCU UAAATT TTGACUGGCCUUCGCGAAU UU-5

TABLE 89 628-646 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 89-1 Unmodified siRNA ++ 89% 0% 5-UUAAAGGGCGAGAAGACCGTT TTAAUUUCCCGCUCUUCUGGC-5 89-2 Random modification (2′-O-methyl) +++ 67% 47% 5-UUAAAGGGCGAGAAGACCGTT TTAAUUUCCCGCUCUUCUGGC-5 89-3A Specific modification (2′-O-methyl) +++ 85% 3% 5-U UA AAGGGCGAGAAGACCGTT TTAAU UUCCCGCUCUUCUGGC-5 89-3B Specific modification (2′-O-methyl) +++ 87% 0% 5-U UAAAGGGCGAGAAGACCGTT TTAAU UUCCCGCUCUUCUGGC-5

TABLE 90 1257-1275 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 90-1 Unmodified siRNA + 77% 0% 5-GAAGAGCCUACACAACCCUTT TTCUUCUCGGAUGUGUUGGGA-5 90-2 Random modification (2′-O-methyl) ++ 50% 27% 5-GAAGAGCCUACACAACCCUTT TTCUUCUCGGAUGUGUUGGGA-5 90-3A Specific modification (2′-O-methyl) ++ 75% 5% 5-GAAGAGCC UA CACAACCCUTT TTCUUCUCGGAU GUGUUGGGA-5 90-3B Specific modification (2′-O-methyl) ++ 76% 1% 5-GAAGAGCC UA CACAACCCUTT TTCUUCUCGGAU GUGUUGGGA-5

TABLE 91 1288-1306 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 91-1 Unmodified siRNA + 83% 0% 5-CUAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5 91-2 Random modification (2′-deoxy-2′-fluoro) ++ 61% 25% 5-CUAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5 91-3A Specific modification (2′-deoxy-2′-fluoro) ++ 78% 6% 5-C UAGAGGAUCUUGAAGACCTT TTGAU CUCCUAGAACUUCUGG-5 91-3B Specific modification (2′-deoxy-2′-fluoro) ++ 81% 1% 5-C UAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5

TABLE 92 1427-1445 BP rat(NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 92-1 Unmodified siRNA + 91% 0% 5-ACAUAGAGGAAGACGCGGATT TTUGUAUCUCCUUCUGCGCCU-5 92-2 Random modification (2′-deoxy-2′-fluoro) +++ 57% 34% 5-ACAUAGAGGAAGACGCGGATT TTUGUAUCUCCUUCUGCGCCU-5 92-3A Specific modification (2′-deoxy-2′-fluoro) +++ 86% 6% 5-ACA UAGAGGAAGACGCGGATT TTUGU AU CUCCUUCUGCGCCU-5 92-3B Specific modification (2′-deoxy-2′-fluoro) +++ 89% 0% 5-ACAUAGAGGAAGACGCGGATT TTUGUAU CUCCUUCUGCGCCU-5

TABLE 93 2091-2109 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 93-1 Unmodified siRNA + 50% 0% 5-AUCGUCGUCAGGGUAAGGUTT TTUAGCAGCAGUCCCAUUCCA-5 93-2 Random modification (2′-O-methyl) ++ 34% 37% 5-AUCGUCGUCAGGGUAAGGUTT TTUAGCAGCAGUCCCAUUCCA-5 93-3A Specific modification (2′-O-methyl) ++ 47% 4% 5-AUCGUCGUCAGGG UAAGGUTT TTUAGCAGCAGUCCCAU UCCA-5 93-3B Specific modification (2′-O-methyl) ++ 49% 1% 5-AUCGUCGUCAGGG UAAGGUTT TTUAGCAGCAGUCCCAU UCCA-5

TABLE 94 2537-2555 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 94-1 Unmodified siRNA + 48% 0% 5-CUCUGGCCUUUCUCUCUAGTT TTGAGACCGGAAAGAGAGAUC-5 94-2 Random modification (2′-O-methyl) ++ 24% 22% 5-CUCUGGCCUUUCUCUCUAGTT TTGAGACCGGAAAGAGAGAUC-5 94-3A Specific modification (2′-O-methyl) ++ 45% 5% 5-CUCUGGCCUUUCUCUC UAGTT TTGAGACCGGAAAGAGAGAUC-5 94-3B Specific modification (2′-O-methyl) ++ 47% 1% 5-CUCUGGCCUUUCUCUC UAGTT TTGAGACCGGAAAGAGAGAUC-5

TABLE 95 2688-2706 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 95-1 Unmodified siRNA + 73% 0% 5-GACAAGGGAAGGUUAGCCUTT TTCUGUUCCCUUCCAAUCGGA-5 95-2 Random modification (2′-O-methyl) +++ 34% 29% 5-GACAAGGGAAGGUUAGCCUTT TTCUGUUCCCUUCCAAUCGGA-5 95-3A Specific modification (2′-O-methyl) +++ 68% 6% 5-GACAAGGGAAGGU UAGCCUTT TTCUGUUCCCUUCCAAU CGGA-5 95-3B Specific modification (2′-O-methyl) +++ 72% 1% 5-GACAAGGGAAGGU UAGCCUTT TTCUGUUCCCUUCCAAU CGGA-5

TABLE 96 2988-2006 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 96-1 Unmodified siRNA + 48% 0% 5-AGACUAAGCCCAAAAGGGCTT TTUCUGAUUCGGGUUUUCCCG-5 96-2 Random modification (2′-deoxy-2′-fluoro) +++ 26% 21% 5-AGACUAAGCCCAAAAGGGCTT TTUCUGAUUCGGGUUUUCCCG-5 96-3A Specific modification (2′-deoxy-2′-fluoro) +++ 45% 5% 5-AGAC UAAGCCCAAAAGGGCTT TTUCUGAU UCGGGUUUUCCCG-5 96-3B Specific modification (2′-deoxy-2′-fluoro) +++ 47% 1% 5-AGAC UAAGCCCAAAAGGGCTT TTUCUGAU UCGGGUUUUCCCG-5

TABLE 97 3132-3150 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 97-1 Unmodified siRNA + 81% 0% 5-CCUCCCCAUCCCCUUUUAATT TTGGAGGGGUAGGGGAAAAUU-5 97-2 Random modification (2′-O-methyl) ++ 48% 44% 5-CCUCCCCAUCCCCUUUUAATT TTGGAGGGGUAGGGGAAAAUU-5 97-3A Specific modification (2′-O-methyl) ++ 80% 4% 5-CCUCCCCAUCCCCUUU UAATT TTGGAGGGGUAGGGGAAA AUU-5 97-3B Specific modification (2′-O-methyl) ++ 80% 0% 5-CCUCCCCAUCCCCUUUUAATT TTGGAGGGGUAGGGGAAA AUU-5

TABLE 98 3471-3489 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 98-1 Unmodified siRNA + 73% 0% 5-AUCAGAGGGAGGUCUUAGATT TTUAGUCUCCCUCCAGAAUCU-5 98-2 Random modification (2′-O-methyl) ++ 19% 32% 5-AUCAGAGGGAGGUCUUAGATT TTUAGUCUCCCUCCAGAAUCU-5 98-3A Specific modification (2′-O-methyl) ++ 68% 6% 5-AUCAGAGGGAGGUCU UAGATT TTUAGUCUCCCUCCAGAAU CU-5 98-3B Specific modification (2′-O-methyl) ++ 69% 1% 5-AUCAGAGGGAGGUCU UAGATT TTUAGUCUCCCUCCAGAAU CU-5

TABLE 99 3477-3495 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 99-1 Unmodified siRNA + 84% 0% 5-GGGAGGUCUUAGAAAACACTT TTCCCUCCAGAAUCUUUUGUG-5 99-2 Random modification (2′-O-methyl) ++ 17% 31% 5-GGGAGGUCUUAGAAAACACTT TTCCCUCCAGAAUCUUUUGUG-5 99-3A Specific modification (2′-O-methyl) ++ 84% 3% 5-GGGAGGUCU UAGAAAACACTT TTCCCUCCAGAAU CUUUUGUG-5 99-3B Specific modification (2′-O-methyl) ++ 82% 0% 5-GGGAGGUCUUAGAAAACACTT TTCCCUCCAGAAU CUUUUGUG-5

TABLE 100 3613-3631 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 100-1 Unmodified siRNA + 71% 0% 5-GGCUUAGUCACUCCUCUUCTT TTCCGAAUCAGUGAGGAGAAG-5 100-2 Random modification (2′-deoxy-2′-fluoro) ++ 23% 14% 5-GGCUUAGUCACUCCUCUUCTT TTCCGAAUCAGUGAGGAGAAG-5 100-3A Specific modification (2′-deoxy-2′-fluoro) ++ 68% 4% 5-GGCU UAGUCACUCCUCUUCTT TTCCGAAU CAGUGAGGAGAAG-5 100-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 1% 5-GGCU UAGUCACUCCUCUUCTT TTCCGAAU CAGUGAGGAGAAG-5

TABLE 101 42-60 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 101-1 Unmodified siRNA + 77% 0% 5-ACCUUAAGGACCACCGGAUTT TTUGGAAUUCCUGGUGGCCUA-5 101-2 Random modification (2′-O-methyl) ++ 52% 24% 5-ACCUUAAGGACCACCGGAUTT TTUGGAAUUCCUGGUGGCCUA-5 101-3A Specific modification (2′-O-methyl) ++ 72% 6% 5-ACCU UAAGGACCACCGGAUTT TTUGGAAU UCCUGGUGGCCUA-5 101-3B Specific modification (2′-O-methyl) ++ 74% 1% 5-ACCU UAAGGACCACCGGAUTT TTUGGAAU UCCUGGUGGCCUA-5

TABLE 102 56-74 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 102-1 Unmodified siRNA + 73% 0% 5-CGGAUCUACACCUUCAAGATT TTGCCUAGAUGUGGAAGUUCU-5 102-2 Random modification (2′-O-methyl) ++ 46% 19% 5-CGGAUCUACACCUUCAAGATT TTGCCUAGAUGUGGAAGUUCU-5 102-3A Specific modification (2′-O-methyl) ++ 68% 5% 5-CGGAUC UA CACCUUCAAGATT TTGCCUAGAU GUGGAAGUUCU-5 102-3B Specific modification (2′-O-methyl) ++ 69% 1% 5-CGGAUC UACACCUUCAAGATT TTGCCUAGAU GUGGAAGUUCU-5

TABLE 103 145-163 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 103-1 Unmodified siRNA + 57% 0% 5-UACCGAGAAUGAGCCUGAUTT TTAUGGCUCUUACUCGGACUA-5 103-2 Random modification (2′-O-methyl) +++ 23% 27% 5-UACCGAGAAUGAGCCUGAUTT TTAUGGCUCUUACUCGGACUA-5 103-3A Specific modification (2′-O-methyl) +++ 54% 6% 5- UACCGAGAAUGAGCCUGAUTT TTAU GGCUCUUACUCGGACUA-5 103-3B Specific modification (2′-O-methyl) +++ 55% 1% 5- UACCGAGAAUGAGCCUGAUTT TTAU GGCUCUUACUCGGACUA-5

TABLE 104 183-201 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 104-1 Unmodified siRNA + 38% 0% 5-GCUUUAAGGAACUGGAAGGTT TTCGAAAUUCCUUGACCUUCC-5 104-2 Random modification (2′-O-methyl) ++ 25% 19% 5-GCUUUAAGGAACUGGAAGGTT TTCGAAAUUCCUUGACCUUCC-5 104-3A Specific modification (2′-O-methyl) ++ 37% 3% 5-GCUU UAAGGAACUGGAAGGTT TTCGAAAU UCCUUGACCUUCC-5 104-3B Specific modification (2′-O-methyl) ++ 37% 0% 5-GCUUUAAGGAACUGGAAGGTT TTCGAAAU UCCUUGACCUUCC-5

TABLE 105 247-265 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 105-1 Unmodified siRNA + 86% 0% 5-UCCUCGUCGUCUGUUCUAATT TTAGGAGCAGCAGACAAGAUU-5 105-2 Random modification (2′-O-methyl) +++ 63% 35% 5-UCCUCGUCGUCUGUUCUAATT TTAGGAGCAGCAGACAAGAUU-5 105-3A Specific modification (2′-O-methyl) +++ 82% 4% 5-UCCUCGUCGUCUGUUC UAATT TTAGGAGCAGCAGACAAGAU U-5 105-3B Specific modification (2′-O-methyl) +++ 84% 1% 5-UCCUCGUCGUCUGUUC UAATT TTAGGAGCAGCAGACAAGAU U-5

TABLE 106 260-278 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 106-1 Unmodified siRNA ++ 73% 0% 5-UUCUAACCGGGCAGCUUCUTT TTAAGAUUGGCCCGUCGAAGA-5 106-2 Random modification (2′-deoxy-2′-fluoro) +++ 61% 37% 5-UUCUAACCGGGCAGCUUCUTT TTAAGAUUGGCCCGUCGAAGA-5 106-3A Specific modification (2′-deoxy-2′-fluoro) +++ 71% 5% 5-UUC UAACCGGGCAGCUUCUTT TTAAGAU UGGCCCGUCGAAGA-5 106-3B Specific modification (2′-deoxy-2′-fluoro) +++ 72% 1% 5-UUC UAACCGGGCAGCUUCUTT TTAAGAU UGGCCCGUCGAAGA-5

TABLE 107 920-938 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 107-1 Unmodified siRNA + 95% 0% 5-GAGGAUGGAUUCGACUUAGTT TTCUCCUACCUAAGCUGAAUC-5 107-2 Random modification (2′-O-methyl) ++ 23% 22% 5-GAGGAUGGAUUCGACUUAGTT TTCUCCUACCUAAGCUGAAUC-5 107-3A Specific modification (2′-O-methyl) ++ 91% 6% 5-GAGGAUGGAUUCGACU UAGTT TTCUCCUACCUAAGCUGAAU C-5 107-3B Specific modification (2′-O-methyl) ++ 94% 0% 5-GAGGAUGGAUUCGACUUAGTT TTCUCCUACCUAAGCUGAAU C-5

TABLE 108 1240-1258 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 108-1 Unmodified siRNA + 67% 0% 5-UAAAGCUGGAAAGGGACGGTT TTAUUUCGACCUUUCCCUGCC-5 108-2 Random modification (2′-O-methyl) ++ 29% 28% 5-UAAAGCUGGAAAGGGACGGTT TTAUUUCGACCUUUCCCUGCC-5 108-3A Specific modification (2′-O-methyl) ++ 65% 4% 5- UAAAGCUGGAAAGGGACGGTT TTAU UUCGACCUUUCCCUGCC-5 108-3B Specific modification (2′-O-methyl) ++ 67% 1% 5- UAAAGCUGGAAAGGGACGGTT TTAU UUCGACCUUUCCCUGCC-5

TABLE 109 1336-1354 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 109-1 Unmodified siRNA + 45% 0% 5-GGAAGUAAGGACCAGAGACTT TTCCUUCAUUCCUGGUCUCUG-5 109-2 Random modification (2′-O-methyl) ++ 23% 27% 5-GGAAGUAAGGACCAGAGACTT TTCCUUCAUUCCUGGUCUCUG-5 109-3A Specific modification (2′-O-methyl) ++ 41% 4% 5-GGAAG UAAGGACCAGAGACTT TTCCUUCAU UCCUGGUCUCUG-5 109-3B Specific modification (2′-O-methyl) ++ 44% 1% 5-GGAAG UAAGGACCAGAGACTT TTCCUUCAU UCCUGGUCUCUG-5

TABLE 110 1862-1880 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 110-1 Unmodified siRNA ++ 70% 0% 5-AAGGCCAACCGAUACUUCUTT TTUUCCGGUUGGCUAUGAAGA-5 110-2 Random modification (2′-deoxy-2′-fluoro) +++ 46% 24% 5-AAGGCCAACCGAUACUUCUTT TTUUCCGGUUGGCUAUGAAGA-5 110-3A Specific modification (2′-deoxy-2′-fluoro) +++ 68% 5% 5-AAGGCCAACCGA UACUUCUTT TTUUCCGGUUGGCUAU GAAGA-5 110-3B Specific modification (2′-deoxy-2′-fluoro) +++ 69% 1% 5-AAGGCCAACCGA UACUUCUTT TTUUCCGGUUGGCUAU GAAGA-5

TABLE 111 2489-2507 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 111-1 Unmodified siRNA + 67% 0% 5-GUUCACGUCCUACCCCUUUTT TTCAAGUGCAGGAUGGGGAAA-5 111-2 Random modification (2′-deoxy-2′-fluoro) ++ 23% 27% 5-GUUCACGUCCUACCCCUUUTT TTCAAGUGCAGGAUGGGGAAA-5 111-3A Specific modification (2′-deoxy-2′-fluoro) ++ 65% 5% 5-GUUCACGUCC UACCCCUUUTT TTCAAGUGCAGGAU GGGGAAA-5 111-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 0% 5-GUUCACGUCCUACCCCUUUTT TTCAAGUGCAGGAU GGGGAAA-5

TABLE 112 3572-3590 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 112-1 Unmodified siRNA + 71% 0% 5-AGAGUUGGGAUUAGGGCUUTT TTUCUCAACCCUAAUCCCGAA-5 112-2 Random modification (2′-O-methyl) ++ 45% 19% 5-AGAGUUGGGAUUAGGGCUUTT TTUCUCAACCCUAAUCCCGAA-5 112-3A Specific modification (2′-O-methyl) ++ 68% 4% 5-AGAGUUGGGAU UAGGGCUUTT TTUCUCAACCCUAAU CCCGAA-5 112-3B Specific modification (2′-O-methyl) ++ 69% 0% 5-AGAGUUGGGAUUAGGGCUUTT TTUCUCAACCCUAAU CCCGAA-5

TABLE 113 3694-3712 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 113-1 Unmodified siRNA + 81% 0% 5-UUACAAAGGAUCUCCUCCCTT TTAAUGUUUCCUAGAGGAGGG-5 113-2 Random modification (2′-O-methyl) ++ 57% 31% 5-UUACAAAGGAUCUCCUCCCTT TTAAUGUUUCCUAGAGGAGGG-5 113-3A Specific modification (2′-O-methyl) ++ 78% 5% 5-U UA CAAAGGAUCUCCUCCCTT TTAAU GUUUCCUAGAGGAGGG-5 113-3B Specific modification (2′-O-methyl) ++ 69% 1% 5-U UACAAAGGAUCUCCUCCCTT TTAAU GUUUCCUAGAGGAGGG-5

TABLE 114 5159-5177 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 114-1 Unmodified siRNA + 70% 0% 5-AACAGCCUUACCCCGAUUCTT TTUUGUCGGAAUGGGGCUAAG-5 114-2 Random modification (2′-O-methyl) ++ 32% 24% 5-AACAGCCUUACCCCGAUUCTT TTUUGUCGGAAUGGGGCUAAG-5 114-3A Specific modification (2′-O-methyl) ++ 68% 4% 5-AACAGCCU UACCCCGAUUCTT TTUUGUCGGAAU GGGGCUAAG-5 114-3B Specific modification (2′-O-methyl) ++ 69% 0% 5-AACAGCCUUACCCCGAUUCTT TTUUGUCGGAAU GGGGCUAAG-5

TABLE 115 5166-5184 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 115-1 Unmodified siRNA + 84% 0% 5-UUACCCCGAUUCAGCCUCUTT TTAAUGGGGCUAAGUCGGAGA-5 115-2 Random modification (2′-deoxy-2′-fluoro) ++ 67% 24% 5-UUACCCCGAUUCAGCCUCUTT TTAAUGGGGCUAAGUCGGAGA-5 115-3A Specific modification (2′-deoxy-2′-fluoro) ++ 82% 3% 5-U UACCCCGAUUCAGCCUCUTT TTAAU GGGGCUAAGUCGGAGA-5 115-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 1% 5-U UACCCCGAUUCAGCCUCUTT TTA AUGGGGCUAAGUCGGAGA-5

TABLE 116 5695-5713 BP mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 116-1 Unmodified siRNA + 75% 0% 5-UAACCCCAAGAACGGGCUUTT TTAUUGGGGUUCUUGCCCGAA-5 116-2 Random modification (2′-deoxy-2′-fluoro) ++ 47% 25% 5-UAACCCCAAGAACGGGCUUTT TTAUUGGGGUUCUUGCCCGAA-5 116-3A Specific modification (2′-deoxy-2′-fluoro) ++ 72% 6% 5- UAACCCCAAGAACGGGCUUTT TTAU UGGGGUUCUUGCCCGAA-5 116-3B Specific modification (2′-deoxy-2′-fluoro) ++ 73% 1% 5- UAACCCCAAGAACGGGCUUTT TTAU UGGGGUUCUUGCCCGAA-5

TABLE 117 aspergillus AF293protein (XM_748400) 499-517 BP (SEQ ID NO: 10) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 117-1 Unmodified siRNA + 57% 0% 5-CUAGUCGAAAGAAAACGGGTT TTGAUCAGCUUUCUUUUGCCC-5 117-2 Random modification (2′-O-methyl) ++ 23% 19% 5-CUAGUCGAAAGAAAACGGGTT TTGAUCAGCUUUCUUUUGCCC-5 117-3A Specific modification (2′-O-methyl) ++ 55% 6% 5-C UAGUCGAAAGAAAACGGGTT TTGAU CAGCUUUCUUUUGCCC-5 117-3B Specific modification (2′-O-methyl) ++ 56% 1% 5-C UAGUCGAAAGAAAACGGGTT TTGAU CAGCUUUCUUUUGCCC-5

TABLE 118 aspergillus AF293protein (XM_748400) 1214-1232 BP (SEQ ID NO: 10) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 118-1 Unmodified siRNA + 46% 0% 5-AGGACGGUACUUUCGAAAGTT TTUCCUGCCAUGAAAGCUUUC-5 118-2 Random modification (2′-O-methyl) ++ 17% 51% 5-AGGACGGUACUUUCGAAAGTT TTUCCUGCCAUGAAAGCUUUC-5 118-3A Specific modification (2′-O-methyl) ++ 44% 6% 5-AGGACGG UACUUUCGAAAGTT TTUCCUGCCAU GAAAGCUUUC-5 118-3B Specific modification (2′-O-methyl) ++ 46% 0% 5-AGGACGGUACUUUCGAAAGTT TTUCCUGCC AUGAAAGCUUUC-5

TABLE 119 Aspergillus AF293 protein XM_748400) 1234-1252 BP (SEQ ID NO: 10) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 119-1 Unmodified siRNA + 97% 0% 5-GUAUCCGAAGACGAAGCUATT TTCAUAGGCUUCUGCUUCGAU-5 119-2 Random modification (2′-O-methyl) +++ 30% 31% 5-GUAUCCGAAGACGAAGCUATT TTCAUAGGCUUCUGCUUCGAU-5 119-3A Specific modification (2′-O-methyl) +++ 92% 8% 5-G UAUCCGAAGACGAAGC UATT TTCAU AGGCUUCUGCUUCGAU -5 119-3B Specific modification (2′-O-methyl) +++ 95% 1% 5-GUAUCCGAAGACGAAGC UATT TTCAU AGGCUUCUGCUUCGAU -5

TABLE 120 Aspergillus AF293 protein (XM_748400) 14-32 BP (SEQ ID NO: 10) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 120-1 Unmodified siRNA + 91% 0% 5-AGAGAGGUGGAGGUAUCUCTT TTUCUCUCCACCUCCAUAGAG-5 120-2 Random modification (2′-O-methyl) ++ 67% 24% 5-AGAGAGGUGGAGGUAUCUCTT TTUCUCUCCACCUCCAUAGAG-5 120-3A Specific modification (2′-O-methyl) ++ 87% 8% 5-AGAGAGGUGGAGG UAUCUCTT TTUCUCUCCACCUCCAU AGAG-5 120-3B Specific modification (2′-O-methyl) ++ 90% 1% 5-AGAGAGGUGGAGG UAUCUCTT TTUCUCUCCACCUCCAU AGAG-5

TABLE 121 Aspergillus AF293 protein XM_748400) 103-121 BP (SEQ ID NO: 10) Locus Expression gene SIRNA Stability inhibition ratio Growth inhibition ratio 121-1 Unmodified siRNA + 58% 0% 5-GAAAACGCUUGUAAAGCCGTT TTCUUUUGCGAACAUUUCGGC-5 121-2 Random modification (2′-O-methyl) ++ 23% 24% 5-GAAAACGCUUGUAAAGCCGTT TTCUUUUGCGAACAUUUCGGC-5 121-3A Specific modification (2′-O-methyl) ++ 54% 5% 5-GAAAACGCUUG UAAAGCCGTT TTCUUUUGCGAAC AU UUCGGC-5 121-3B Specific modification (2′-O-methyl) ++ 56% 0% 5-GAAAACGCUUGUAAAGCCGTT TTCUUUUGCGAACAU UUCGGC-5

TABLE 122 Aspergillus AF293protein(XM_748400) 493-511 BP (SEQ ID NO: 10) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 122-1 Unmodified siRNA + 81% 0% 5-GCUGAACUAGUCGAAAGAATT TTCGACUUGAUCAGCUUUCUU-5 122-2 Random modification (2′-deoxy-2′-fluoro) ++ 49% 29% 5-GCUGAACUAGUCGAAAGAATT TTCGACUUGAUCAGCUUUCUU-5 122-3A Specific modification (2′-deoxy-2′-fluoro) ++ 78% 3% 5-GCUGAAC UAGUCGAAAGAATT TTCGACUUGAU CAGCUUUCUU-5 122-3B Specific modification (2′-deoxy-2′-fluoro) ++ 79% 1% 5-GCUGAAC UAGUCGAAAGAATT TTCGACUUGAU CAGCUUUCUU-5

TABLE 123 Aspergillus AF293 protein (XM_748400) 537-555 BP (SEQ ID NO: 10) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 123-1 Unmodified siRNA + 38% 0% 5-GGAAGAAGAUAGAGCAUCCTT TTCCUUCUUCUAUCUCGUAGG-5 123-2 Random modification (2′-deoxy-2′-fluoro) ++ 13% 19 5-GGAAGAAGAUAGAGCAUCCTT TTCCUUCUUCUAUCUCGUAGG-5 123-3A Specific modification (2′-deoxy-2′-fluoro) ++ 37% 4% 5-GGAAGAAGA UAGAGCAUCCTT TTCCUUCUUCUAU CUCGUAGG-5 123-3B Specific modification (2′-deoxy-2′-fluoro) ++ 37% 0% 5-GGAAGAAGAUAGAGCAUCCTT TTCCUUCUUCUAU CUCGUAGG-5

TABLE 124 Aspergillus AF293 protein XM_748400) 623-641 BP (SEQ ID NO: 10) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 124-1 Unmodified siRNA + 79% 0% 5-AUCUACCCAGCUCUCCCUUTT TTUAGAUGGGUCGAGAGGGAA-5 124-2 Random modification (2′-O-methyl) ++ 43% 21% 5-AUCUACCCAGCUCUCCCUUTT TTUAGAUGGGUCGAGAGGGAA-5 124-3A Specific modification (2′-O-methyl) ++ 75% 6% 5-AUC UACCCAGCUCUCCCUUTT TTUAGAU GGGUCGAGAGGGAA-5 124-3B Specific modification (2′-O-methyl) ++ 77% 1% 5-AUC UACCCAGCUCUCCCUUTT TTUAGAU GGGUCGAGAGGGAA-5

TABLE 125 Aspergillus AF293protein (XM_748400) 1096-1114 BP (SEQ ID NO: 10) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 125-1 Unmodified siRNA + 87% 0% 5-AGCGAUCCCGAACAAGUAUTT TTUCGCUAGGGCUUGUUCAUA-5 125-2 Random modification (2′-O-methyl) ++ 34% 25% 5-AGCGAUCCCGAACAAGUAUTT TTUCGCUAGGGCUUGUUCAUA-5 125-3A Specific modification (2′-O-methyl) ++ 84% 4% 5-AGCGAUCCCGAACAAG UAUTT TTUCGCUAGGGCUUGUUCAU A-5 125-3B Specific modification (2′-O-methyl) ++ 85% 0% 5-AGCGAUCCCGAACAAGUAUTT TTUCGCUAGGGCUUGUUCAU A-5

TABLE 126 Aspergillus AF293 protein (XM_748400) 1227-1245 BP (SEQ ID NO: 10) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 126-1 Unmodified siRNA + 77% 0% 5-CGAAAGUGUAUCCGAAGACTT TTGCUUUCACAUAGGCUUCUG-5 126-2 Random modification (2′-deoxy-2′-fluoro) ++ 41% 22% 5-CGAAAGUGUAUCCGAAGACTT TTGCUUUCACAUAGGCUUCUG-5 126-3A Specific modification (2′-deoxy-2′-fluoro) ++ 75% 3% 5-CGAAAGUG UAUCCGAAGACTT TTGCUUUCAC AU AGGCUUCUG-5 126-3B Specific modification (2′-deoxy-2′-fluoro) ++ 69% 0% 5-CGAAAGUGUAUCCGAAGACTT TTGCUUUCACAU AGGCUUCUG-5

TABLE 127 Aspergillus AF293 protein (XM_748400) 1238-1256 BP (SEQ ID NO: 10) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 127-1 Unmodified siRNA + 48% 0% 5-CCGAAGACGAAGCUAUGAATT TTGGCUUCUGCUUCGAUACUU-5 127-2 Random modification (2′-deoxy-2′-fluoro) ++ 23% 19% 5-CCGAAGACGAAGCUAUGAATT TTGGCUUCUGCUUCGAUACUU-5 127-3A Specific modification (2′-deoxy-2′-fluoro) ++ 46% 2% 5-CCGAAGACGAAGC UA UGAATT TTGGCUUCUGCUUCGAU ACUU-5 127-3B Specific modification (2′-deoxy-2′-fluoro) ++ 47% 0% 5-CCGAAGACGAAGCUAUGAATT TTGGCUUCUGCUUCGAU ACUU-5

TABLE 128 Human BIC (NR_001458.3) 170-188 BP (SEQ ID NO: 1) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 128-1 Unmodified siRNA + 83% 0% 5-UCUCCCACCCAAUGGAGAU TTAGAGGGUGGGUUACCUCUA-5 128-2 Random modification (2′-O-methyl) ++ 49% 24% 5-UCUCCCACCCAAUGGAGAU TTAGAGGGUGGGUUACCUCUA-5 128-3A Specific modification (2′-O-methyl) ++ 78% 9% 5-UCUCC CACC CA AUGGAGAU TTAGAGGGU GGGUUACCUCUA-5 128-3B Specific modification (2′-O-methyl) ++ 81% 4% 5-UCUCCCACCCAAUGGAGAU TTAGAGGGUGGGUUACCUCUA-5

TABLE 129 206-224 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 129-1 Unmodified siRNA + 69% 0% 5-AAACCAGGAAGGGGAAAUCTT TTUUUGGUCCUUCCCCUUUAG-5 129-2 Random modification (2′-deoxy-2′-fluoro) ++ 42% 41% 5-AAACCAGGAAGGGGAAAUCTT TTUUUGGUCCUUCCCCUUUAG-5 129-3A Specific modification (2′-deoxy-2′-fluoro) ++ 61% 9% 5-AAAC CA GGAAGGGGAAAUCTT TTUUUG GU CCUUCCCCUUUAG-5 129-3B Specific modification (2′-deoxy-2′-fluoro) ++ 64% 3% 5-AAAC CA GGAAGGGGAAAUCTT TTUUUGGUCCUUCCCCUUUAG-5

TABLE 130 213-231 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 130-1 Unmodified siRNA + 66% 0% 5-GAAGGGGAAAUCUGUGGUUTT TTCUUCCCCUUUAGACACCAA-5 130-2 Random modification (2′-O-methyl) +++ 41% 24% 5-GAAGGGGAAAUCUGUGGUUTT TTCUUCCCCUUUAGACACCAA-5 130-3A Specific modification (2′-O-methyl) +++ 61% 6% 5-GAAGGGGAAAUC UGUG GUUTT TTCUUCCCCUUUAG ACAC CAA-5 130-3B Specific modification (2′-O-methyl) +++ 65% 2% 5-GAAGGGGAAAUC UGUGGUUTT TTCUUCCCCUUUAGACAC CAA-5

TABLE 131 398-416 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 131-1 Unmodified siRNA + 86% 0% 5-GGGAGGAUGACAAAGAAGCTT TTCCCUCCUACUGUUUCUUCG-5 131-2 Random modification (2′-deoxy-2′-fluoro) ++ 37% 19% 5-GGGAGGAUGACAAAGAAGCTT TTCCCUCCUACUGUUUCUUCG-5 131-3A Specific modification (2′-deoxy-2′-fluoro) ++ 78% 9% 5-GGGAGGA UG A CAAAGAAGCTT TTCCCUCCUAC UGU UUCUUCG-5 131-3B Specific modification (2′-deoxy-2′-fluoro) ++ 84% 2% 5-GGGAGGA UGA CAAAGAAGCTT TTCCCUCCUACUGU UUCUUCG-5

TABLE 132 170-188 BP Human BIC (NR_001458.3) (SEQ ID NO: 1) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 132-1 Unmodified siRNA + 90% 0% 5-GAAACUGGUACUUUCCCCCTT TTCUUUGACCAUGAAAGGGGG-5 132-2 Random modification (2′-O-methyl) ++ 57% 24% 5-GAAACUGGUACUUUCCCCCTT TTCUUUGACCAUGAAAGGGGG-5 132-3A Specific modification (2′-O-methyl) ++ 85% 7% 5-GAAAC UG G UACUUUCCCCCTT TTCUUUG AC CAU GAAAGGGGG-5 132-3B Specific modification (2′-O-methyl) ++ 88% 3% 5-GAAAC UG G UACUUUCCCCCTT TTCUUUGACCAU GAAAGGGGG-5

TABLE 133 13-31 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 133-1 Unmodified siRNA + 72% 0% 5-AUCGCUGCUCCUCCUCCUCTT TTUAGCGACGAGGAGGAGGAG-5 133-2 Random modification (2′-deoxy-2′-fluoro) ++ 39% 24% 5-AUCGCUGCUCCUCCUCCUCTT TTUAGCGACGAGGAGGAGGAG-5 133-3A Specific modification (2′-deoxy-2′-fluoro) ++ 69% 6% 5-AUCGC UGCUCCUCCUCCUCTT TTUAGCGAC GAGGAGGAGGAG-5 133-3B Specific modification (2′-deoxy-2′-fluoro) ++ 71% 1% 5-AUCGC UGCUCCUCCUCCUCTT TTUAGCGAC GAGGAGGAGGAG-5

TABLE 134 239-257 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 134-1 Unmodified siRNA + 39% 0% 5-AGCUCUUUGUCACCUCUCUTT TTUCGAGAAACAGUGGAGAGA-5 134-2 Random modification (2′-O-methyl) ++ 19% 24% 5-AGCUCUUUGUCACCUCUCUTT TTUCGAGAAACAGUGGAGAGA-5 134-3A Specific modification (2′-O-methyl) ++ 34% 9% 5-AGCUCUU UGU CACCUCUCUTT TTUCGAGAAAC AGU GGAGAGA-5 134-3B Specific modification (2′-O-methyl) ++ 37% 3% 5-AGCUCUUUGUCA CCUCUCUTT TTUCGAGAA AC AGUGGAGAGA-5

TABLE 135 294-312 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 135-1 Unmodified siRNA + 58% 0% 5-AAUAAGCAGCUCGCGCUCCTT TTUUAUUCGUCGAGCGCGAGG-5 135-2 Random modification (2′-O-methyl) ++ 32% 24% 5-AAUAAGCAGCUCGCGCUCCTT TTUUAUUCGUCGAGCGCGAGG-5 135-3A Specific modification (2′-O-methyl) ++ 51% 9% 5-AA UAAG CAGCUCGCGCUCCTT TTUUAU UCGU CGAGCGCGAGG-5 135-3B Specific modification (2′-O-methyl) ++ 54% 2% 5-AA UAAG CAGCUCGCGCUCCTT TTUUAU UCGUCGAGCGCGAGG-5

TABLE 136 1383-1401 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 136-1 Unmodified siRNA + 97% 0% 5-CUAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5 136-2 Random modification (2′-deoxy-2′-fluoro) ++ 38% 29% 5-CUAGAGGAUCUUGAAGACCTT TTGAUCUCCUAGAACUUCUGG-5 136-3A Specific modification (2′-deoxy-2′-fluoro) ++ 91% 5% 5-C UAGAGGAUCU UGAAGACCTT TTGAU CUCCUAGAAC UUCUGG-5 136-3B Specific modification (2′-deoxy-2′-fluoro) ++ 95% 1% 5-CUAGAGGAUCUUGAAGACCTT TTGAU CUCCUAGAAC UUCUGG-5

TABLE 137 2151-2169 BP Human KAZRIN (NM_201628) (SEQ ID NO: 2) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 137-1 Unmodified siRNA + 32% 0% 5-AUCGACCUGAAGGAGUACGTT TTUAGCUGGACUUCCUCAUGC-5 137-2 Random modification (2′-O-methyl) ++ 19% 24% 5-AUCGACCUGAAGGAGUACGTT TTUAGCUGGACUUCCUCAUGC-5 137-3A Specific modification (2′-O-methyl) ++ 29% 6% 5-AUCGACC UGAAGGAG UACGTT TTUAGCUGGAC UUCCUCAU GC-5 137-3B Specific modification (2′-O-methyl) ++ 30% 1% 5-AUCGACC UGAAGGAG UACGTT TTUAGCUGGACUUCCUCAU GC-5

TABLE 138 80-98 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 138-1 Unmodified siRNA + 75% 0% 5-CCCUCCCCUGUCCCCGCUUTT TTGGGAGGGGACAGGGGCGAA-5 138-2 Random modification (2′-deoxy-2′-fluoro) ++ 41% 34%  5-CCCUCCCCUGUCCCCGCUUTT TTGGGAGGGGACAGGGGCGAA-5 138-3A Specific modification (2′-deoxy-2′-fluoro) ++ 72% 3% 5-CCCUCCCC UGUCCCCGCUUTT TTGGGAGGGGAC AGGGGCGAA-5 138-3B Specific modification (2′-deoxy-2′-fluoro) ++ 73% 1% 5-CCCUCCCC UGUCCCCGCUUTT TTGGGAGGGGACAGGGGCGAA-5

TABLE 139 431-449 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 139-1 Unmodified siRNA + 94% 0% 5-UUUGAUCAGCGGAGACUCGTT TTAAACUAGUCGCCUCUGAGC-5 139-2 Random modification (2′-O-methyl) ++ 49% 31%  5-UUUGAUCAGCGGAGACUCGTT TTAAACUAGUCGCCUCUGAGC-5 139-3A Specific modification (2′-O-methyl) ++ 89% 3% 5-UU UGAU CAGCGGAGACUCGTT TTAAAC UAGU CGCCUCUGAGC-5 139-3B Specific modification (2′-O-methyl) ++ 82% 0.5%   5-UUUG AU CAGCGGAGACUCGTT TTAAACUAGUCGCCUCUGAGC-5

TABLE 140 591-609 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 140-1 Unmodified siRNA + 93% 0% 5-AGUUAACCCGGGACUUGGATT TTUCAAUUGGGCCCUGAACCU-5 140-2 Random modification (2′-O-methyl) ++ 45% 34%  5-AGUUAACCCGGGACUUGGATT TTUCAAUUGGGCCCUGAACCU-5 140-3A Specific modification (2′-O-methyl) ++ 90% 3% 5-AGU UAACCCGGGACU UGGATT TTUCAAU UGGGCCCUGAAC CU-5 140-3B Specific modification (2′-O-methyl) ++ 91% 1% 5-AGU UAACCCGGGACUUGGATT TTUCAAUUGGGCCCUGAAC CU-5

TABLE 141 669-687 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 141-1 Unmodified siRNA + 77% 0% 5-AUCACAAACCCCUAGAGGGTT TTUAGUGUUUGGGGAUCUCCC-5 141-2 Random modification (2′-O-methyl) ++ 35% 31%  5-AUCACAAACCCCUAGAGGGTT TTUAGUGUUUGGGGAUCUCCC-5 141-3A Specific modification (2′-O-methyl) ++ 75% 4% 5-AU CACAAACCCC UAGAGGGTT TTUAGUGU UUGGGGAU CUCCC-5 141-3B Specific modification (2′-O-methyl) ++ 75% 1% 5-AU CACAAACCCCUAGAGGGTT TTUAGUGUUUGGGGAU CUCCC-5

TABLE 142 674-692 BP Human CDKN1B (NM_004064) (SEQ ID NO: 3) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 142-1 Unmodified siRNA + 84% 0% 5-AAACCCCUAGAGGGCAAGUTT TTUUUGGGGAUCUCCCGUUCA-5 142-2 Random modification (2′-deoxy-2′-fluoro) ++ 37% 29%  5-AAACCCCUAGAGGGCAAGUTT TTUUUGGGGAUCUCCCGUUCA-5 142-3A Specific modification (2′-deoxy-2′-fluoro) ++ 82% 5% 5-AAACCCC UAGAGGG CAAGUTT TTUUUGGGGAU CUCCCGU UCA-5 142-3B Specific modification (2′-deoxy-2′-fluoro) ++ 83% 1% 5-AAACCCC UAGAGGG CAAGUTT TTUUUGGGGAUCUCCCGUUCA-5

TABLE 143 Chinpanzee SOD2 (NM_001009022) 45-63 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 143-1 Unmodified siRNA + 70%  0% 5-GGAACCUCACAUCAACGCGCATT TTCCUUGGAGUGUAGUUGCGCGU-5 143-2 Random modification (2′-deoxy-2′-fluoro) ++ 21% 43% 5-GGAACCUCACAUCAACGCGCATT TTCCUUGGAGUGUAGUUGCGCGU-5 143-3A Specific modification (2′-deoxy-2′-fluoro) ++ 52% 11% 5-GGAACCU CACAU CAACGCG CATT TTCCUUGGAGUGU AGU UGCGCGU -5 143-3B Specific modification (2′-deoxy-2′-fluoro) ++ 65%  4% 5-GGAACCU CACAUCAACGCGCATT TTCCUUGGAGUGU AGU UGCGC GU-5

TABLE 144 Chimpanzee SOD2 (NM_001009022) 116-134 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 144-1 Unmodified siRNA + 87% 0% 5-UGAACGUCACCGAGGAGAATT TTACUUGCAGUGGCUCCUCUU-5 144-2 Random modification (2′-O-methyl) ++ 65% 24%  5-UGAACGUCACCGAGGAGAATT TTACUUGCAGUGGCUCCUCUU-5 144-3A Specific modification (2′-O-methyl) ++ 82% 5% 5- UGAACGU CACCGAGGAGAATT TTAC UUGCAGU GGCUCCUCUU-5 144-3B Specific modification (2′-O-methyl) ++ 85% 1% 5-UGAACGU CACCGAGGAGAATT TTAC UUGCAGUGGCUCCUCUU-5

TABLE 145 Chimpanzee SOD2 (NM_001009022) 266-284 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 145-1 Unmodified siRNA + 97% 0% 5-AACCCAAAGGGGAGUUGCUTT TTUUGGGUUUCCCCUCAACGA-5 145-2 Random modification (2′-O-methyl) ++ 37% 49%  5-AACCCAAAGGGGAGUUGCUTT TTUUGGGUUUCCCCUCAACGA-5 145-3A Specific modification (2′-O-methyl) ++ 92% 6% 5-AACC CAAAGGGGAGU UGCUTT TTUUGGGU UUCCCCUCAAC GA-5 145-3B Specific modification (2′-O-methyl) ++ 83% 1% 5-AACCCAAAGGGGAGU UGCUTT TTUUGGGU UUCCCCUCAACGA-5

TABLE 146 Chimpanzee SOD2 (NM_001009022) 274-292 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 146-1 Unmodified siRNA + 77% 0% 5-AAAGGGGAGUUGCUGGAAGTT TTUUUCCCCUCAACGACCUUC-5 146-2 Random modification (2′-O-methyl) ++ 47% 31%  5-AAAGGGGAGUUGCUGGAAGTT TTUUUCCCCUCAACGACCUUC-5 146-3A Specific modification (2′-O-methyl) ++ 74% 4% 5-AAAGGGGAGU UGC UGGAAGTT TTUUUCCCCUCAAC GAC CUUC-5 146-3B Specific modification (2′-O-methyl) ++ 76% 1% 5-AAAGGGGAGU UGCUGGAAGTT TTUUUCCCCUCAACGAC CUUC-5

TABLE 147 Chimpanzee SOD2 (NM_001009022) 295-313 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 147-1 Unmodified siRNA + 86% 0% 5-AAACGUGACUUUGGUUCCUTT TTUUUGCACUGAAACCAAGGA-5 147-2 Random modification (2′-O-methyl) ++ 37% 29%  5-AAACGUGACUUUGGUUCCUTT TTUUUGCACUGAAACCAAGGA-5 147-3A Specific modification (2′-O-methyl) ++ 82% 5% 5-AAACG UGACUU UGGUUCCUTT TTUUUGCAC UGAAAC CAAGGA-5 147-3B Specific modification (2′-O-methyl) ++ 83% 1% 5-AAACGUGACUU UGGUUCCUTT TTUUUGCAC UGAAACCAAGGA-5

TABLE 148 Chimpanzee SOD2 (NM_001009022) 108-126 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 148-1 Unmodified siRNA + 72%  0% 5-GAAUAACCUGAACGUCACCTT TTCUUAUUGGACUUGCAGUGG-5 148-2 Random modification (2′-O-methyl) ++ 21% 19% 5-GAAUAACCUGAACGUCACCTT TTCUUAUUGGACUUGCAGUGG-5 148-3A Specific modification (2′-O-methyl) ++ 69% 10% 5-GAA UAACC UGAACGU CACCTT TTCUUAU UGGAC UUGCAGU GG-5 148-3B Specific modification (2′-O-methyl) ++ 71%  3% 5-GAA UAACCUGAACGU CACCTT TTCUUAUUGGAC UUGCAGUGG-5

TABLE 149 Chimpanzee SOD2 (NM_001009022) 119-137 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 149-1 Unmodified siRNA + 81% 0% 5-ACGUCACCGAGGAGAAGUATT TTUGCAGUGGCUCCUCUUCAU-5 149-2 Random modification (2′-O-methyl) ++ 31% 26%  5-ACGUCACCGAGGAGAAGUATT TTUGCAGUGGCUCCUCUUCAU-5 149-3A Specific modification (2′-O-methyl) ++ 75% 6% 5-ACGU CACCGAGGAGAAG UA TT TTUGCAGU GGCUCCUCUUC AU -5 149-3B Specific modification (2′-O-methyl) ++ 80% 1% 5-ACGU CACCGAGGAGAAGUATT TTUGCAGU GGCUCCUCUUCAU -5

TABLE 150 Chimpanzee SOD2 (NM_001009022) 131-149 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 150-1 Unmodified siRNA + 62% 0% 5-AGAAGUACCAGGAGGCGUUTT TTUCUUCAUGGUCCUCCGCAA-5 150-2 Random modification (2′-deoxy-2′-fluoro) ++ 39% 35%  5-AGAAGUACCAGGAGGCGUUTT TTUCUUCAUGGUCCUCCGCAA-5 150-3A Specific modification (2′-deoxy-2′-fluoro) ++ 57% 3% 5-AGAAG UAC CAGGAGGCGUUTT TTUCUUCAU GGU CCUCCGCAA-5 150-3B Specific modification (2′-deoxy-2′-fluoro) ++ 60% 1% 5-AGAAG UACCAGGAGGCGUUTT TTUCUUCAUGGU CCUCCGCAA-5

TABLE 151 Chimpanzee SOD2 (NM_001009022) 240-258 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 151-1 Unmodified siRNA + 71% 0% 5-AAACCUCAGCCCUAACGGUTT TTUUUGGAGUCGGGAUUGCCA-5 151-2 Random modification (2′-O-methyl) ++ 28% 27%  5-AAACCUCAGCCCUAACGGUTT TTUUUGGAGUCGGGAUUGCCA-5 151-3A Specific modification (2′-O-methyl) ++ 70% 3% 5-AAACCU CAGCCC UAACGGUTT TTUUUGGAGU CGGGAU UGCCA-5 151-3B Specific modification (2′-O-methyl) ++ 70% 1% 5-AAACCUCA GCCCUAACGGUTT TTUUUGGAGUCGGGAU UGCCA-5

TABLE 152 chimpanzee SOD2 (NM_001009022) 323-341 BP (SEQ ID NO: 4) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 152-1 Unmodified siRNA + 87% 0% 5-UUAAGGAGAAGCUGACGGCTT TTAAUUCCUCUUCGACUGCCG-5 152-2 Random modification (2′-O-methyl) ++ 45% 24%  5-UUAAGGAGAAGCUGACGGCTT TTAAUUCCUCUUCGACUGCCG-5 152-3A Specific modification (2′-O-methyl) ++ 82% 4% 5-U UAAGGAGAAGC UG ACGGCTT TTAAU UCCUCUUCGAC UGCCG-5 152-3B Specific modification (2′-O-methyl) ++ 83% 1% 5-U UAAGGAGAAGCUGACGGCTT TTAAU UCCUCUUCGAC UGCCG-5

TABLE 153 rhesus monkey RECEPTOR (XM_001111972) 3-21 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 153-1 Unmodified siRNA + 75% 0% 5-AACUUCUGGGAGCCUCCAATT TTUUGAAGACCCUCGGAGGUU-5 153-2 Random modification (2′-O-methyl) ++ 42% 27% 5-AACUUCUGGGAGCCUCCAATT TTUUGAAGACCCUCGGAGGUU-5 153-3A Specific modification (2′-O-methyl) ++ 69% 4% 5-AACUUC UGGGAGCCUC CAATT TTUUGAAGAC CCUCGGAGGU U-5 153-3B Specific modification (2′-O-methyl) ++ 73% 1% 5-AACUUCUGGGAGCCUC CAATT TTUUGAAGAC CCUCGGAGGUU-5

TABLE 154 Rhesus monkey RECEPTOR (XM_001111972) 80-98 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 154-1 Unmodified siRNA + 87% 0% 5-CCAGCGAGCCCAAAAGAAATT TTGGUCGCUCGGGUUUUCUUU-5 154-2 Random modification (2′-deoxy-2′-fluoro) ++ 35% 24% 5-CCAGCGAGCCCAAAAGAAATT TTGGUCGCUCGGGUUUUCUUU-5 154-3A Specific modification (2′-deoxy-2′-fluoro) ++ 82% 5% 5-C CAGCGAGCC CAAAAGAAATT TTGGU CGCUCGGGU UUUCUUU-5 154-3B Specific modification (2′-deoxy-2′-fluoro) ++ 85% 1% 5-C CAGCGAGCC CAAAAGAAATT TTGGUCGCUCGGGUUUUCUUU-5

TABLE 155 Rhesus monkey RECEPTOR (XM_001111972) 216-234 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 155-1 Unmodified siRNA + 86% 0% 5-CUCAAAUCAAGGCCGGAGUTT TTGAGUUUAGUUCCGGCCUCA-5 155-2 Random modification (2′-O-methyl) ++ 36% 34% 5-CUCAAAUCAAGGCCGGAGUTT TTGAGUUUAGUUCCGGCCUCA-5 155-3A Specific modification (2′-O-methyl) ++ 82% 4% 5-CU CAAAU CAAGGCCGGAGUTT TTGAGU UUAGU UCCGGCCUCA-5 155-3B Specific modification (2′-O-methyl) ++ 85% 1% 5-CUCAAAUCAAGGCCGGAGUTT TTGAGU UUAGU UCCGGCCUCA-5

TABLE 156 Rhesus monkey RECEPTOR (XM_001111972) 13-31 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 156-1 Unmodified siRNA + 71% 0% 5-AGCCUCCAAACUCCUAGCUTT TTUCGGAGGUUUGAGGAUCGA-5 156-2 Random modification (2′-O-methyl) ++ 47% 19% 5-AGCCUCCAAACUCCUAGCUTT TTUCGGAGGUUUGAGGAUCGA-5 156-3A Specific modification (2′-O-methyl) ++ 65% 3% 5-AGCCUC CAAACUCC UAGCUTT TTUCGGAGGU UUGAGGAU CGA-5 156-3B Specific modification (2′-O-methyl) ++ 70% 1% 5-AGCCUCCAAACUCCUAGCUTT TTUCGGAGGU UUGAGGAU CGA-5

TABLE 157 Rhesus monkey RECEPTOR (XM_001111972) 162-180 BP (SEQ ID NO: 5) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 157-1 Unmodified siRNA + 73% 0% 5-AUACUUGGCGGGCUCUUUCTT TTUAUGAACCGCCCGAGAAAG-5 157-2 Random modification (2′-O-methyl) ++ 25% 31% 5-AUACUUGGCGGGCUCUUUCTT TTUAUGAACCGCCCGAGAAAG-5 157-3A Specific modification (2′-O-methyl) ++ 70% 4% 5-A UACU UG GCGGGCUCUUUCTT TTUAU GAAC CGCCCGAGAAAG-5 157-3B Specific modification (2′-O-methyl) ++ 72% 1% 5-AUA CUUGGCGGGCUCUUUCTT TTUAUGAAC CGCCCGAGAAAG-5

TABLE 158 Dog B cell lymphoma (NM_001003016) 508-526 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 158-1 Unmodified siRNA + 84% 0% 5-UUGGGGAAGCGGCCGGCGGTT TTAACCCCUUCGCCGGCCGCC-5 158-2 Random modification (2′-O-methyl) ++ 36% 27% 5-UUGGGGAAGCGGCCGGCGGTT TTAACCCCUUCGCCGGCCGCC-5 158-3A Specific modification (2′-O-methyl) ++ 78% 5% 5-U UG GGGAAGCGGCCGGCGGTT TTAAC CCCUUCGCCGGCCGCC-5 158-3B Specific modification (2′-O-methyl) ++ 82% 1% 5-U UGGGGAAGCGGCCGGCGGTT TTAAC CCCUUCGCCGGCCGCC-5

TABLE 159 Dog Bcell lymphoma (NM_001003016) 794-812 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 159-1 Unmodified siRNA + 96% 0% 5-AAGGCAUGCUUCGGAAACUTT TTUUCCGUACGAAGCCUUUGA-5 159-2 Random modification (2′-O-methyl) ++ 60% 35% 5-AAGGCAUGCUUCGGAAACUTT TTUUCCGUACGAAGCCUUUGA-5 159-3A Specific modification (2′-O-methyl) ++ 87% 6% 5-AAGG CAUG CUUCGGAAACUTT TTUUCCGUAC GAAGCCUUUGA-5 159-3B Specific modification (2′-O-methyl) ++ 95% 1% 5-AAGG CAUGCUUCGGAAACUTT TTUUCCGUAC GAAGCCUUUGA-5

TABLE 160 Dog B cell lymphoma (NM_001003016) 801-819 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 160-1 Unmodified siRNA + 91% 0% 5-GCUUCGGAAACUGGACAUCTT TTCGAAGCCUUUGACCUGUAG-5 160-2 Random modification (2′-deoxy-2′-fluoro) ++ 29% 37% 5-GCUUCGGAAACUGGACAUCTT TTCGAAGCCUUUGACCUGUAG-5 160-3A Specific modification (2′-deoxy-2′-fluoro) ++ 87% 5% 5-GCUUCGGAAAC UG GA CAUCTT TTCGAAGCCUUUG AC CUGU AG-5 160-3B Specific modification (2′-deoxy-2′-fluoro) ++ 90% 1% 5-GCUUCGGAAACUGGA CAUCTT TTCGAAGCCUUUGAC CUGU AG-5

TABLE 161 Dog Bcell lymphoma (NM_001003016) 21-39 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 161-1 Unmodified siRNA + 73% 0% 5-AACUCUACUGUGGAGUCGGTT TTUUGAGAUGACACCUCAGCC-5 161-2 Random modification (2′-deoxy-2′-fluoro) ++ 25% 31% 5-AACUCUACUGUGGAGUCGGTT TTUUGAGAUGACACCUCAGCC-5 161-3A Specific modification (2′-deoxy-2′-fluoro) ++ 65% 8% 5-AACUC UAC UGUGGAGUCGGTT TTUUGAGAU GACAC CUCAGCC-5 161-3B Specific modification (2′-deoxy-2′-fluoro) ++ 72% 2% 5-AACUCUAC UGUGGAGUCGGTT TTUUGAGAU GACAC CUCAGCC-5

TABLE 162 Dog Bcell lymphoma (NM_001003016) 124-142 BP (SEQ ID NO: 6) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 162-1 Unmodified siRNA + 87% 0% 5-AGAAACGCAGUAAUCCGGATT TTUCUUUGCGUCAUUAGGCCU-5 162-2 Random modification (2′-O-methyl) ++ 36% 27% 5-AGAAACGCAGUAAUCCGGATT TTUCUUUGCGUCAUUAGGCCU-5 162-3A Specific modification (2′-O-methyl) ++ 78% 5% 5-AGAAACG CAG UA AUCCGGATT TTUCUUUGCGU CAU UAGGCCU-5 162-3B Specific modification (2′-O-methyl) ++ 82% 1% 5-AGAAACGCAG UAAUCCGGATT TTUCUUUGCGU CAUUAGGCCU-5

TABLE 163 rat (NM_001014070.1) 447-465 BP (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 163-1 Unmodified siRNA + 55% 0% 5-GGAAGUCCACCUUCUCCGATT TTCCUUCAGGUGGAAGAGGCU-5 163-2 Random modification (2′-O-methyl) ++ 27% 31% 5-GGAAGUCCACCUUCUCCGATT TTCCUUCAGGUGGAAGAGGCU-5 163-3A Specific modification (2′-O-methyl) ++ 51% 5% 5-GGAAGUC CA CCUUCUCCGATT TTCCUUCAGGU GGAAGAGGCU-5 163-3B Specific modification (2′-O-methyl) ++ 54% 1% 5-GGAAGUCCA CCUUCUCCGATT TTCCUUCAGGU GGAAGAGGCU-5

TABLE 164 rat (NM_001014070.1) 460-478 BP (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 164-1 Unmodified siRNA + 73% 0% 5-CUCCGACAGAUGAAGGAAATT TTGAGGCUGUCUACUUCCUUU-5 164-2 Random modification (2′-O-methyl) ++ 46% 21% 5-CUCCGACAGAUGAAGGAAATT TTGAGGCUGUCUACUUCCUUU-5 164-3A Specific modification (2′-O-methyl) ++ 70% 6% 5-CUCCGA CA GA UGAAGGAAATT TTGAGGCU GU CUAC UUCCUUU-5 164-3B Specific modification (2′-O-methyl) ++ 72% 1% 5-CUCCGACAGA UGAAGGAAATT TTGAGGCUGU CUACUUCCUUU-5

TABLE 165 rat (NM_001014070.1) 487-505 BP (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 165-1 Unmodified siRNA + 83% 0% 5-AAGGACCUAGAGGAGUCACTT TTUUCCUGGAUCUCCUCAGUG-5 165-2 Random modification (2′-O-methyl) ++ 36% 27% 5-AAGGACCUAGAGGAGUCACTT TTUUCCUGGAUCUCCUCAGUG-5 165-3A Specific modification (2′-O-methyl) ++ 78% 5% 5-AAGGACC UAGAGGAGU CA CTT TTUUCCUGGAU CUCCUCAGU G-5 165-3B Specific modification (2′-O-methyl) ++ 80% 1% 5-AAGGACC UAGAGGAGUCACTT TTUUCCUGGAUCUCCUCAGU G-5

TABLE 166 614-632 BP rat (NM_001014070.1) (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 166-1 Unmodified siRNA + 90% 0% 5-CUGACCGGAAGCGCUUAAATT TTGACUGGCCUUCGCGAAUUU-5 166-2 Random modification (2′-deoxy-2′-fluoro) ++ 59% 24% 5-CUGACCGGAAGCGCUUAAATT TTGACUGGCCUUCGCGAAUUU-5 166-3A Specific modification (2′-deoxy-2′-fluoro) ++ 85% 4% 5-C UGACCGGAAGCGCU UAAATT TTGAC UGGCCUUCGCGAAU UU-5 166-3B Specific modification (2′-deoxy-2′-fluoro) ++ 87% 1% 5-C UGACCGGAAGCGCUUAAATT TTGACUGGCCUUCGCGAAU UU-5

TABLE 167 rat (NM_001014070.1) 1257-1275 BP (SEQ ID NO: 7) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 167-1 Unmodified siRNA + 76% 0% 5-GAAGAGCCUACACAACCCUTT TTCUUCUCGGAUGUGUUGGGA-5 167-2 Random modification (2′-O-methyl) ++ 43% 31% 5-GAAGAGCCUACACAACCCUTT TTCUUCUCGGAUGUGUUGGGA-5 167-3A Specific modification (2′-O-methyl) ++ 74% 10% 5-GAAGAGCC UACACAACCCUTT TTCUUCUCGGAUGUGU UGGGA-5 167-3B Specific modification (2′-O-methyl) ++ 74% 3% 5-GAAGAGCCUACACAACCCUTT TTCUUCUCGGAUGUGU UGGGA-5

TABLE 168 364-382 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 168-1 Unmodified siRNA + 65% 0% 5-ACAGAAAGAGUUCGAGGAGTT TTUGUCUUUCUCAAGCUCCUC-5 168-2 Random modification (2′-O-methyl) ++ 37% 28% 5-CACAGAAAGAGUUCGAGGAGTT TTUGUCUUUCUCAAGCUCCUC-5 168-3A Specific modification (2′-O-methyl) ++ 61% 6% 5-A CA GAAAGAGUUCGAGGAGTT TTUGU CUUUCUCAAGCUCCUC-5 168-3B Specific modification (2′-O-methyl) ++ 64% 1% 5-A CAGAAAGAGUUCGAGGAGTT TTUGU CUUUCUCAAGCUCCUC-5

TABLE 169 527-545 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 169-1 Unmodified siRNA + 0% 0% 5-AGGAGACCGUGACAUUUCGTT TTUCCUCUGGCACUGUAAAGC-5 169-2 Random modification (2′-deoxy-2′-fluoro) +++ 33% 5-AGGAGACCGUGACAUUUCGTT 24% TTUCCUCUGGCACUGUAAAGC-5 169-3A Specific modification (2′-deoxy-2′-fluoro) +++ 69% 6% 5-AGGAGACCG UGA CAUUUCGTT TTUCCUCUGGC ACUGU AAAGC-5 169-3B Specific modification (2′-deoxy-2′-fluoro) +++ 72% 3% 5-AGGAGACCG UGA C AUUUCGTT TTUCCUCUGGCACUGU AAAGC-5

TABLE 170 42-60 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 170-1 Unmodified siRNA + 73% 0% 5-ACCUUAAGGACCACCGGAUTT TTUGGAAUUCCUGGUGGCCUA-5 170-2 Random modification (2′-deoxy-2′-fluoro) ++ 41% 25% 5-ACCUUAAGGACCACCGGAUTT TTUGGAAUUCCUGGUGGCCUA-5 170-3A Specific modification (2′-deoxy-2′-fluoro) ++ 70% 8% 5-ACCU UAAGGAC CA CCGGAUTT TTUGGA AU UCCUG GU GGCCUA-5 170-3B Specific modification (2′-deoxy-2′-fluoro) ++ 71% 1% 5-ACCU UAAGGACCACCGGAUTT TTUGGAAUUCCUGGU GGCCUA-5

TABLE 171 56-74 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 171-1 Unmodified siRNA + 44% 0% 5-CGGAUCUACACCUUCAAGATT TTGCCUAGAUGUGGAAGUUCU-5 171-2 Random modification (2′-O-methyl) ++ 29% 27% 5-CGGAUCUACACCUUCAAGATT TTGCCUAGAUGUGGAAGUUCU-5 171-3A Specific modification (2′-O-methyl) ++ 40% 9% 5-CGGAUC UACACCUU CAAGATT TTGCCUAGAUGU GGAAGU UCU-5 171-3B Specific modification (2′-O-methyl) ++ 42% 2% 5-CGGAUC UACACCUUCA AGATT TTGCCUAGAUGU GGAAGU UCU-5

TABLE 172 183-201 BP Rat BIRC5 (NM_022274) (SEQ ID NO: 8) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 172-1 Unmodified siRNA + 77% 0% 5-GCUUUAAGGAACUGGAAGGTT TTCGAAAUUCCUUGACCUUCC-5 172-2 Random modification (2′-O-methyl) ++ 51% 29% 5-GCUUUAAGGAACUGGAAGGTT TTCGAAAUUCCUUGACCUUCC-5 172-3A Specific modification (2′-O-methyl) ++ 72% 8% 5-GCUU UA AGGAAC UGGAAGGTT TTCGAA AU UCCUUGAC CUUCC-5 172-3B Specific modification (2′-O-methyl) ++ 74% 1% 5-GCUUUA AGGAAC UGGAAGGTT TTCGAAAUUCCUUGAC CUUCC-5

TABLE 173 290-308 BP Mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 173-1 Unmodified siRNA + 75% 0% 5-GAGAGAGACGGUGGAAGAATT TTCUCUCUCUGCCACCUUCUU-5 173-2 Random modification (2′-O-methyl) +++ 56% 22% 5-GAGAGAGACGGUGGAAGAATT TTCUCUCUCUGCCACCUUCUU-5 173-3A Specific modification (2′-O-methyl) +++ 72% 4% 5-GAGAGAGACGG UG GAAGAATT TTCUCUCUCUGCCAC CUUCUU-5 173-3B Specific modification (2′-O-methyl) +++ 74% 1% 5-GAGAGAGACGGUGGAAGAATT TTCUCUCUCUGCC ACCUUCUU-5

TABLE 174 791-809 BP Mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 174-1 Unmodified siRNA + 53% 0% 5-AUCCUGCAGAAGAAGCCUCTT TTUAGGACGUCUUCUUCGGAG-5 174-2 Random modification (2′-O-methyl) ++ 37% 24% 5-AUCCUGCAGAAGAAGCCUCTT TTUAGGACGUCUUCUUCGGAG-5 174-3A Specific modification (2′-O-methyl) ++ 50% 6% 5-AUCC UGCAGAAGAAGCCUCTT TTUAGGACGU CUUCUUCGGAG-5 174-3B Specific modification (2′-O-methyl) ++ 74% 1% 5-AUCC UGCAGAAGAAGCCUCTT TTUAGGACGUCUUCUUCGGAG-5

TABLE 175 247-265 BP Mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 175-1 Unmodified siRNA + 84% 0% 5-UCCUCGUCGUCUGUUCUAATT TTAGGAGCAGCAGACAAGAUU-5 175-2 Random modification (2′-deoxy-2′-fluoro) ++ 49% 23% 5-UCCUCGUCGUCUGUUCUAATT TTAGGAGCAGCAGACAAGAUU-5 175-3A Specific modification (2′-deoxy-2′-fluoro) ++ 77% 6% 5-UCCUCGUCGUC UG UUC UAATT TTAGGAGCAGCAGAC AAGAU U-5 175-3B Specific modification (2′-deoxy-2′-fluoro) ++ 74% 1% 5-UCCUCGUCGUCUGUUC UAATT TTAGGAGCAGCAGAC AAGAU U-5

TABLE 176 1148-1166 BP Mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 176-1 Unmodified siRNA + 89% 0% 5-AACCCACCACAGCUAGAACUU UUUUGGGUGGUGUCGAUCUUG-5 176-2 Random modification (2′-deoxy-2′-fluoro) +++ 57% 21% 5-AACCCACCACAGCUAGAACUU UUUUGGGUGGUGUCGAUCUUG-5 176-3A Specific modification (2′-deoxy-2′-fluoro) +++ 79% 9% 5-AACC CACCACAGC UAGAACUU UUUUGGGU GGUGU CGAU CUUG-5 176-3B Specific modification (2′-deoxy-2′-fluoro) +++ 86% 1% 5-AACC CACCACAGC UAGAACUU UUUUGGGUGGUGU CGAUCUUG-5

TABLE 177 3694-3712 BP Mice (NM_008960.2) (SEQ ID NO: 9) Locus Expression Growth gene SIRNA Stability inhibition ratio inhibition ratio 177-1 Unmodified siRNA + 77% 0% 5-UUACAAAGGAUCUCCUCCCTT TTAAUGUUUCCUAGAGGAGGG-5 177-2 Random modification (2′-O-methyl) ++ 51% 29% 5-UUACAAAGGAUCUCCUCCCTT TTAAUGUUUCCUAGAGGAGGG-5 177-3A Specific modification (2′-O-methyl) ++ 72% 6% 5-U UACAAAGGAUCUCCUCCCTT TTAAUGU UUCCUAGAGGAGGG-5 177-3B Specific modification (2′-O-methyl) ++ 74% 1% 5-UUACAAAGGAUCUCCUCCCTT TTAAUGUUUCCUAGAGGAGGG-5

TABLE 178 75-93 BP Aspergillus AF293 protein (XM_748400) Locus Expression Growth gene (SEQ ID NO: 10) SIRNA Stability inhibition ratio inhibition ratio 178-1 Unmodified siRNA + 58% 0% 5-AAACGAGAGAGCCCACCUUTT TTUUUGCUCUCUCGGGUGGAA-5 178-2 Random modification (2′-O-methyl) +++ 37% 27% 5-AAACGAGAGAGCCCACCUUTT TTUUUGCUCUCUCGGGUGGAA-5 178-3A Specific modification (2′-O-methyl) +++ 56% 4% 5-AAACGAGAGAGCC CACCUUTT TTUUUGCUCUCUCGG GU GGAA-5 178-3B Specific modification (2′-O-methyl) +++ 57% 1% 5-AAACGAGAGAGCCCACCUUTT TTUUUGCUCUCUCGGGU GGAA-5

TABLE 179 137-155 BP Aspergillus AF293 protein (XM_748400) Locus Expression Growth gene (SEQ ID NO: 10) SIRNA Stability inhibition ratio inhibition ratio 179-1 Unmodified siRNA + 69% 0% 5-AAAGCGGUGGAUCAGCUCUTT TTUUUCGCCACCUAGUCGAGA-5 179-2 Random modification (2′-O-methyl) ++ 43% 24% 5-AAAGCGGUGGAUCAGCUCUTT TTUUUCGCCACCUAGUCGAGA-5 179-3A Specific modification (2′-O-methyl) ++ 63% 10% 5-AAAGCGG UG GAU CAGCUCUTT TTUUUCGCC AC CUAGU CGAGA-5 179-3B Specific modification (2′-O-methyl) ++ 67% 1% 5-AAAGCGGUGGAUCAGCUCUTT TTUUUCGCCAC CUAGU CGAGA-5

TABLE 180 360-378 BP Aspergillus AF293 protein(XM_748400) Locus Expression Growth gene (SEQ ID NO: 10) SIRNA Stability inhibition ratio inhibition ratio 180-1 Unmodified siRNA + 71% 0% 5-UCCAAGCUUCCUCGUUGGUTT TTAGGUUCGAAGGAGCAACCA-5 180-2 Random modification (2′-deoxy-2′-fluoro) ++ 51% 28% 5-UCCAAGCUUCCUCGUUGGUTT TTAGGUUCGAAGGAGCAACCA-5 180-3A Specific modification (2′-deoxy-2′-fluoro) ++ 65% 7% 5-UC CAAGCUUCCUCGU UG GUTT TTAGGU UCGAAGGAGCA AC CA-5 180-3B Specific modification (2′-deoxy-2′-fluoro) ++ 71% 0% 5-UCCAAGCUUCCUCGUUGGUTT TTAGGU UCGAAGGAGCAAC CA-5

TABLE 181 14-32 BP Aspergillus AF293 protein (XM_748400) Locus Expression Growth gene (SEQ ID NO: 10) SIRNA Stability inhibition ratio inhibition ratio 181-1 Unmodified siRNA + 90% 0% 5-AGAGAGGUGGAGGUAUCUCTT TTUCUCUCCACCUCCAUAGAG-5 181-2 Random modification (2′-deoxy-2′-fluoro) +++ 68% 26% 5-AGAGAGGUGGAGGUAUCUCTT TTUCUCUCCACCUCCAUAGAG-5 181-3A Specific modification (2′-deoxy-2′-fluoro) +++ 85% 7% 5-AGAGAGG UGGAGG UAUCUCTT TTUCUCUCC AC CUCCAU AGAG-5 181-3B Specific modification (2′-deoxy-2′-fluoro) +++ 88% 1% 5-AGAGAGG UGGAGGUAUCUCTT TTUCUCUCCACCUCCAU AGAG-5

TABLE 182 1238-1256 BP Aspergillus AF293 protein (XM_748400) Locus Expression Growth gene (SEQ ID NO: 10) SIRNA Stability inhibition ratio inhibition ratio 182-1 Unmodified siRNA + 73% 0% 5-CCGAAGACGAAGCUAUGAATT TTGGCUUCUGCUUCGAUACUU-5 182-2 Random modification (2′-O-methyl) +++ 51% 29% 5-CCGAAGACGAAGCUAUGAATT TTGGCUUCUGCUUCGAUACUU-5 182-3A Specific modification (2′-O-methyl) +++ 69% 6% 5-CCGAAGACGAAGC UAUGAATT TTGGCUUCUGCUUCGAUAC UU-5 182-3B Specific modification (2′-O-methyl) +++ 71% 1% 5-CCGAAGACGAAGC UAUGAATT TTGGCUUCUGCUUCGAUAC UU-5 In tables 1-182: Chemically modified nucleotides were indicated by bold letters of “A”, “U”, “G” or “C”; “+” indicates the situation that after serum treatment, the main siRNA band disappeared completely, while evident siRNA degradation bands were observed; “++” indicates the situation that after serum treatment, the main siRNA band remains visible although degradaion occurs, at the same time, siRNA degradation bands are easily observed; “+++” indicates the situation that after serum treatment, no obvious degradation occurs with the main siRNA band, no siRNA degradation band is observed.

In addition, as shown in table 1-182, the specific siRNA modification strategy provided by the present invention greatly improves serum stability of the siRNAs; while at the same time, reduces their cytotoxicity and does not compromise their gene silencing activity.

Thus, the present invention can achieve siRNA stabilization with minimal chemical modifications, decreases their potential cytotoxicity and influence on gene silencing activity. 

1. A modified oligonucleotide comprising a first nucleic acid fragment and a second nucleic acid fragment, the first nucleic acid fragment and the second nucleic acid fragment can form double-stranded region, wherein the modified oligonucleotide has at least one of the following modifications, the modification(s) improve the stability of the modified oligonucleotide in mammalian body fluids; (a) The first nucleic acid fragment contains at least one contiguous UA sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence in the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the complementary UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s); wherein at least one of the nucleotides in at least one of the UA/UA site(s) is a modified nucleotide; (b) The first nucleic acid fragment contains at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous CA or UG sequence complementary to the CA or UG sequence in the first nucleic acid fragment, the CA or UG sequence(s) of the first nucleic acid fragment and the CA or UG sequence(s) of the second nucleic acid fragment pair to form CA/UG and/or UG/CA site(s); wherein at least one of the nucleotides in at least one of the CA/UG and/or UG/CA site(s) is a modified nucleotide; (c) The first nucleic acid fragment contains at least one contiguous UA sequence and at least one contiguous CA or UG sequence, the second nucleic acid fragment contains at least one contiguous UA sequence complementary to the UA sequence of the first nucleic acid fragment and one contiguous CA or UG sequence complementary to the CA or UG sequence of the first nucleic acid fragment, the UA sequence(s) of the first nucleic acid fragment and the UA sequence(s) of the second nucleic acid fragment pair to form UA/UA site(s), the CA or UG sequence(s) of the first nucleic acid fragment and the UG or CA sequence(s) of the second nucleic acid fragment pair to form CA/UG or UG/CA site(s); wherein at least one of the nucleotides in at least one of the UA/UA site(s) is a modified nucleotide, and at least one of the nucleotides in at least one of the CA/UG or UG/CA site(s) is a modified nucleotide.
 2. The modified oligonucleotide of claim 1, wherein the oligonucleotide contains at least one UA/UA and/or CA/UG and/or UG/CA site(s).
 3. The modified oligonucleotide of claim 1, wherein only one uridine nucleotide in all occurrences of the UA/UA site(s) is a modified nucleotide.
 4. The modified oligonucleotide of claim 1, wherein only cytidine nucleotide(s) in all occurrences of the CA/UG or UG/CA site is/are modified nucleotide(s).
 5. The modified oligonucleotide of claim 1, wherein all the nucleotides are unmodified nucleotides except the nucleotides in said CA/UG and/or UA/UA and/or UG/CA site(s).
 6. The modified oligonucleotide of claim 1, wherein the first nucleic acid fragment and the second nucleic acid fragment are in two separate nucleic acid strands or in a single nucleic acid strand.
 7. The modified oligonucleotide of claim 6, wherein the modified oligonucleotide is a hairpin-structured and single-stranded nucleic acid molecule, the complementary nucleic acid sequences of the first nucleic acid fragment and the second nucleic acid fragment pair to form double-stranded region.
 8. The modified oligonucleotide of claim 6, wherein the modified oligonucleotide contains a sense strand and an antisense strand, the sense strand and the antisense strand are contiguous nucleic acid fragments; the first nucleic acid fragment is in the sense strand, and the second nucleic acid fragment is in the antisense strand.
 9. The modified oligonucleotide of claim 6, wherein the modified oligonucleotide contains a sense strand and an antisense strand, the sense strand contains two or more discontiguous sense-strand component fragments, the antisense strand is a contiguous nucleic acid fragment; the first nucleic acid fragment is in one or more sense-strand component fragments, the second nucleic acid fragment is in the antisense strand.
 10. The modified oligonucleotide of claim 1, wherein the modified oligonucleotide is a hybrid nucleic acid molecule comprising ribonucleotides and at least one deoxyribonucleotide.
 11. The modified oligonucleotide of claim 1, wherein the modified oligonucleotide has at least one of the following modifications: (a) modifying the phosphodiester bond(s) connecting nucleotides in the oligonucleotide; (b) modifying the sugar(s) of the nucleotide in the oligonucleotide; (c) modifying the base(s) of the nucleotide in the oligonucleotide.
 12. The modified oligonucleotide of claim 11, wherein the modification is replacing a 2′-OH group on the sugar with a 2′-modified nucleotide.
 13. The modified oligonucleotide of claim 12, wherein the modification is replacing a 2′-OH group on the sugar with a 2′-O-methyl group or a 2′-deoxy-2′-fluoro group.
 14. A pharmaceutical composition for inhibiting the expression of a target gene in a mammal, wherein the pharmaceutical composition comprises at least one modified oligonucleotide of claim 1, and a pharmaceutically acceptable carrier.
 15. A method for preparing the pharmaceutical composition of claim 14, wherein the method comprises formulating the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
 16. A method for inhibiting the expression of a target gene in a cell, comprising: (a) introducing the oligonucleotide of claim 1 into the cell; and (b) incubating the cell for a time sufficient to obtain inhibition of the expression of the target gene in the cell.
 17. The method of claim 16, wherein the cell is a mammalian cell.
 18. A method for preparing an oligonucleotide that is highly stable in a biological sample and can inhibit the expression of a target gene, comprising: (a) selecting one or more nucleic acid sequences of between 18 and 30 nucleotides in length from the nucleotide sequence of the mRNA resulting from the transcription of the target gene; and (b) synthesizing the selected sequences, wherein one strand comprises a sequence complementary to selected sequence in (a); and (c) testing one or more oligonucleotides of (b) for their activity to inhibit the expression of the target gene in a biological sample; and (d) selecting one or more oligonucleotides of (c) possessing the activity to inhibit the expression of the target gene in a biological sample; and (e) in the oligonucleotides selected in (d), identifying in the nucleotide sequences of all occurrences of the UA/UA, CA/UG and UG/CA site(s); and (f) synthesizing one or more oligonucleotides selected in (d), wherein at least one nucleotide in the UA/UA, CA/UG and UG/CA site(s) identified in (e) is replaced by a corresponding modified nucleotide.
 19. The method of claim 18, wherein only cytidine nucleotide(s) in all occurrences of the CA/UG or UG/CA site is/are modified.
 20. The method of claim 18, wherein only one uridine nucleotide in each UA/UA site is modified.
 21. The method of claim 18, wherein all the nucleotides are unmodified nucleotides except the nucleotides in said CA/UG and/or UA/UA and/or UG/CA site(s).
 22. A method of treating a disease caused by expression of a target gene in a subject, said method comprises administering to a said subject a pharmaceutical composition comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
 23. The method of claim 22, wherein the subject is a human being.
 24. A method for preparing the oligonucleotide with nuclease resistance, said method comprises the steps of: (a) identifying in the nucleotide sequence of the oligonucleotide all occurrences of UA/UA, CA/UG and UG/CA site(s); and (b) synthesizing the oligonucleotide, wherein at least one nucleotide in the UA/UA, CA/UG and UG/CA site(s) identified in (a) is replaced by a modified corresponding nucleotide.
 25. The method of claim 24, wherein only cytidine nucleotide(s) in all occurrences of CA/UG or UG/CA site is/are modified.
 26. The method of claim 24, wherein only one uridine nucleotide in all occurrences of UA/UA site(s) is modified.
 27. The method of claim 24, wherein all the nucleotides are unmodified nucleotides except the nucleotides in said CA/UG and/or UA/UA and/or UG/CA site(s).
 28. A method to identify an oligonucleotide with stability in biological samples, comprises the steps of: (a) providing a first modified oligonucleotide of claim 1, and a second oligonucleotide identical in sequence to the first oligonucleotide except that it does not have modified nucleotide(s) of the oligonucleotide of claim 1; and (b) determining the stability and the degradation process of said first and second oligonucleotide in a biological sample by contacting the two oligonucleotides with the biological sample under identical conditions, Whereby, where the first modified oligonucleotide is degraded less rapidly than the second oligonucleotide, an oligonucleotide with stability in a biological sample is identified. 